Benzothiophene derivatives as estrogen receptor inhibitors

ABSTRACT

A compound of formula (I): 
                         
or a pharmaceutically acceptable salt thereof, compositions, combinations and medicaments containing said compounds and processes for their preparation. The invention also relates to the use of said compounds, combinations, compositions and medicaments, for example as inhibitors of the activity of the estrogen receptor, including degrading the estrogen receptor, the treatment of diseases and conditions mediated by the estrogen receptor.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed pursuant to 35 USC 371 as a United StatesNational Phase Application of International Patent Application SerialNo. PCT/EP2014/063899 filed on Jul. 1, 2014, which claims priority from1311888.0 filed on Jul. 3, 2013 in the United Kingdom.

FIELD OF THE INVENTION

The present invention relates to compounds, compositions, combinationsand medicaments containing said compounds and processes for theirpreparation. The invention also relates to the use of said compounds,combinations, compositions and medicaments, for example as inhibitors ofthe activity of the estrogen receptor, including degrading the estrogenreceptor, the treatment of diseases and conditions mediated by theestrogen receptor, in particular for the treatment of breast cancer.

BACKGROUND OF THE INVENTION

The estrogen receptor (ER) is a member of the nuclear hormone receptorfamily and functions as a ligand-activated transcription factor involvedwith the up and down regulation of gene expression. The natural hormonefor the estrogen receptor is B17-estradiol (E2) and closely relatedmetabolites. Binding of estradiol to the estrogen receptor causes adimerization of the receptor and the dimer in turn binds to estrogenresponse elements (ERE's) on DNA. The ERDNA complex recruits othertranscription factors responsible for the transcription of DNAdownstream from the ERE into mRNA which is eventually translated intoprotein. Alternatively the interaction of ER with DNA may be indirectthrough the intermediacy of other transcription factors, most notablyfos and jun. Since the expression of a large number of genes isregulated by the estrogen receptor and since the estrogen receptor isexpressed in many cell types, modulation of the estrogen receptorthrough binding of either natural hormones or synthetic ER ligands canhave profound effects on the physiology and pathophysiology of theorganism.

A variety of diseases have their aetiology and/or pathology mediated bythe ER. Collectively these diseases are called estrogen-dependentdiseases. Estrogens are critical for sexual development in females. Inaddition, estrogens play an important role in maintaining bone density,regulation of blood lipid levels, and appear to have neuroprotectiveeffects. Consequently decreased estrogen production in post-menopausalwomen is associated with a number of diseases such as osteoporosis,atherosclerosis, depression and cognitive disorders. Conversely certaintypes of proliferative diseases such as breast and uterine cancer andendometriosis are stimulated by estrogens and therefore antiestrogens(i.e. estrogen antagonists) have utility in the prevention and treatmentof these types of disorders.

There are two different forms of the estrogen receptor, usually referredto as α and β, each encoded by a separate gene (ESR1 and ESR2,respectively).

Both ERs are widely expressed in different tissue types, however thereare some notable differences in their expression patterns. The ERα isfound in endometrium, breast cancer cells, ovarian stroma cells, and thehypothalamus. In males, ERα protein is found in the epithelium of theefferent ducts. The expression of the ERβ protein has been documented inkidney, brain, bone, heart, lungs, intestinal mucosa, prostate, andendothelial cells. Development therefore of selective ligands maytherefore preserve the beneficial aspects of estrogen.

Breast Cancer is the most common malignancy to affect women andworldwide, the incidence of the disease is increasing. Estrogens, inparticular, act as endocrine growth factors for at least one-third ofbreast cancers, and depriving the tumour of this stimulus is arecognised therapy for advanced disease In premenopausal women, this isachieved by the ablation of ovarian function through surgical,radiotherapeutic, or medical means and, in postmenopausal women, by theuse of aromatase inhibitors.

An alternative approach to estrogen withdrawal is to antagonise estrogenwith antiestrogens. These are drugs that bind to and compete forestrogen receptors (ER) present in estrogen-responsive tissue.Conventional nonsteroidal antiestrogens, such as tamoxifen, competeefficiently for ER binding but their effectiveness is often limited bythe partial agonism they display, which results in an incompleteblockade of estrogen-mediated activity. A specific or “pure”antiestrogen with high affinity for ER and without any agonist effects,may have advantages over conventional nonsteroidal anti estrogens in thetreatment of estrogen-dependent disease. Fulvestrant is the first of anew class of potent pure anti estrogens and is completely free of thepartial agonist, estrogen-like activity, associated with currentlyavailable antiestrogens like tamoxifen.

It would be desirable to investigate other approaches to antagonise theER receptor.

One approach would be to develop selective ER down regulators ordegraders that reduce ER expression at either the transcript or proteinlevel.

Several methods are available for the manipulation of protein levels,including proteolysis targeting chimeric molecules (PROTACs) whichcontain a ligand that recognizes the target protein linked to a ligandthat binds to a specific E3 ubiquitin ligase. It would be desirable tohave a small molecule which can simultaneously bind ER and an E3ubiquitin ligase and which promotes ubiquitination of ER and leads todegradation of ER by the Proteosome. One suitable E3 ubiquitin ligase isthe von Hippel-Lindau tumour suppressor (VHL).

The present inventors have identified compounds which are capable ofinhibiting estrogen receptor function including compounds which degradethe estrogen receptor.

SUMMARY OF THE INVENTION

In one aspect there is provided a compound of formula (I):

Wherein R¹ is OH, OC₁₋₃alkyl, halogen, H

-   R₂ is OH, OC₁₋₃alkyl-   X is O, CO-   L is a linking group comprising a length of 8-16 atoms in shortest    length-   R₃ is straight chin or branched C₁₋₆alkyl, C₃₋₆ cycloalkyl-   R₄ is 4-methylthiazol-5-yl, oxazol-5-yl, halo-   or a pharmaceutically acceptable salt thereof.

In a further aspect of the present invention, there is provided acompound of formula (I), or a pharmaceutically acceptable salt thereoffor use in therapy, in particular in the treatment of diseases andconditions mediated by the estrogen receptor.

In a further aspect of the present invention, there is provided apharmaceutical composition comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and one or more ofpharmaceutically acceptable carriers, diluents and excipients.

In a further aspect of the present invention, there is provided a methodof treating diseases and conditions mediated by the estrogen receptor ina subject comprising administering a therapeutically effective amount ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.

In a further aspect of the present invention, there is provided the useof a compound of formula (I), or a pharmaceutically acceptable saltthereof in the manufacture of a medicament for use in treating diseasesand conditions mediated by the estrogen receptor.

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent.

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one further therapeutic agent for use in therapy,particularly for treating diseases and conditions mediated by theestrogen receptor.

In a further aspect of the invention there is provided a combinationcomprising compound of formula (I) or a pharmaceutically acceptable saltthereof and at least one further therapeutic agent for use in treatingdiseases and conditions mediated by the estrogen receptor.

In a further aspect there is provided a method of treating diseases andconditions mediated by the estrogen receptor comprising administering toa human in need thereof a therapeutically effective amount of acombination comprising compound of formula (I) or a pharmaceuticallyacceptable salt thereof, and at least one further therapeutic agent.

In a further aspect there is provided the use of a combinationcomprising compound of formula (I) or a pharmaceutically acceptable saltthereof and at least one further therapeutic agent in the manufacture ofa medicament for treating diseases and conditions mediated by theestrogen receptor.

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one anti-neoplastic agent.

In a further aspect there is provided a combination comprising acompound of formula (I) or a pharmaceutically acceptable salt thereofand at least one anti-neoplastic agent, for use in therapy, inparticular for diseases and conditions mediated by the estrogenreceptor.

In a further aspect there is provided a combination comprising acompound of formula (I) or pharmaceutically acceptable salt thereof andat least one anti-neoplastic agent, for use in treating diseases andconditions mediated by the estrogen receptor.

In a further aspect there is provided the use of a combinationcomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof and at least one anti-neoplastic agent, in the manufactureof a medicament for treating diseases and conditions mediated by theestrogen receptor.

In a further aspect there is provided a method of treating diseases andconditions mediated by the estrogen receptor, comprising administeringto a human in need thereof a therapeutically effective amount of acombination comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof and at least one anti-neoplastic agent.

In a further aspect there is provided a pharmaceutical compositioncomprising a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof and at least one furthertherapeutic agent, particularly at least one anti-neoplastic agent andone or more of pharmaceutically acceptable carriers, diluents andexcipients.

In a further aspect there is provided a method of degrading the estrogenreceptor comprising administration comprising administering to a humanin need thereof a therapeutically effective amount of a compound ofFormula (I) or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, “a compound of the invention” includes all solvates,complexes, polymorphs, radiolabelled derivatives, stereoisomers andoptical isomers of the compounds of formula (I) and salts thereof.

As used herein “halo” means fluoro (—F), chloro (—Cl), bromo (—Br) oriodo (—I).

As used herein, the term “effective amount” means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought, forinstance, by a researcher or clinician. Furthermore, the term“therapeutically effective amount” means any amount which, as comparedto a corresponding subject who has not received such amount, results inimproved treatment, healing, prevention, or amelioration of a disease,disorder, or side effect, or a decrease in the rate of advancement of adisease or disorder. The term also includes within its scope amountseffective to enhance normal physiological function.

As used herein, the term “pharmaceutically acceptable” refers to thosecompounds, materials, compositions, and dosage forms which are, withinthe scope of sound medical judgment, suitable for use in contact withthe tissues of human beings and animals without excessive toxicity,irritation, or other problem or complication, commensurate with areasonable benefit/risk ratio.

The compounds of the invention may exist in solid or liquid form. Insolid form, compound of the invention may exist in a continuum of solidstates ranging from fully amorphous to fully crystalline. The term‘amorphous’ refers to a state in which the material lacks long rangeorder at the molecular level and, depending upon the temperature, mayexhibit the physical properties of a solid or a liquid. Typically suchmaterials do not give distinctive X-ray diffraction patterns and, whileexhibiting the properties of a solid, are more formally described as aliquid. Upon heating, a change from solid to liquid properties occurswhich is characterized by a change of state, typically second order(‘glass transition’). The term ‘crystalline’ refers to a solid phase inwhich the material has a regular ordered internal structure at themolecular level and gives a distinctive X-ray diffraction pattern withdefined peaks. Such materials when heated sufficiently will also exhibitthe properties of a liquid, but the change from solid to liquid ischaracterized by a phase change, typically first order (‘meltingpoint’).

The compound of formula (I) may exist in solvated and unsolvated forms.As used herein, the term “solvate” refers to a complex of variablestoichiometry formed by a solute (in this invention, a compound offormula (I) or a salt) and a solvent. Such solvents for the purpose ofthe invention may not interfere with the biological activity of thesolute. The skilled artisan will appreciate that pharmaceuticallyacceptable solvates may be formed for crystalline compounds whereinsolvent molecules are incorporated into the crystalline lattice duringcrystallization. The incorporated solvent molecules may be watermolecules or non-aqueous such as ethanol, isopropanol, DMSO, aceticacid, ethanolamine, and ethyl acetate molecules. Crystalline latticeincorporated with water molecules are typically referred to as“hydrates”. Hydrates include stoichiometric hydrates as well ascompositions containing variable amounts of water. The present inventionincludes all such solvates.

The compounds of the invention may have the ability to crystallize inmore than one form, a characteristic, which is known as polymorphism,and it is understood that such polymorphic forms (“polymorphs”) arewithin the scope of the invention. Polymorphism generally can occur as aresponse to changes in temperature or pressure or both and can alsoresult from variations in the crystallization process. Polymorphs can bedistinguished by various physical characteristics known in the art suchas x-ray diffraction patterns, solubility and melting point.

It is also noted that the compounds of formula (I) may form tautomers.It is understood that all tautomers and mixtures of tautomers of thecompounds of the present invention are included within the scope of thecompounds of the present invention.

As used herein, the term “estrogen receptor inhibitor”, or “inhibitor”refers to any compound or treatment capable of inhibiting or reducingthe expression or activity of the estrogen receptor. The inhibitor ispreferably selective.

-   In one aspect R₄ is 4-methylthiazol-5-yl, oxazol-5-yl.-   In one aspect R₄ is 4-methylthiazol-5-yl;-   In one aspect R₄ is chloro;-   In one aspect R₄ is oxazol-5-yl;-   In one aspect R¹ is OH, F, Br, OCH₃ or H;-   In a further aspect R¹ is OH;-   In one aspect R² is OH or OCH₃;-   In one aspect R² is OH;-   In one aspect the linker group is a straight chain alkylene group of    8-16 carbon atoms wherein one or more carbon atoms are replaced by a    group each independently selected from —O—, —NH—, —N(CH₃)—,

In one aspect the linker group is of formula (ii)—(R⁵CH₂CH₂)_(X)OCH₂  (ii)

-   Wherein each R⁵ is independently selected from —O—, —NH—, —N(CH₃)—    or

-   and x is 2-4-   In one aspect each R⁵ is O;-   In a further aspect the linker is selected from-   (OCH₂CH₂)₄OCH₂-   (OCH₂CH₂)₃OCH₂-   (OCH₂CH₂)₂OCH₂

-   OCH₂CH₂N(CH₃)CH₂CH₂OCH₂CH₂OCH₂-   OCH₂CH₂N(CH₃)(CH₂)₃(OCH₂CH₂)₂OCH₂

While aspects for each variable have generally been listed aboveseparately for each variable this invention includes those compounds inwhich several or each aspect in formula (I) is selected from each of theaspects listed above. Therefore, this invention is intended to includeall combinations of aspects for each variable.

Examples of compounds of the prevent invention include the following:

-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide-   (2S,4R)-4-Hydroxy-1-((S)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-14-(4-((2-(4-Bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-methyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-Ethyl-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-Cyclopropyl-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-Cyclopentyl-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-isobutyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(2-(4-Hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-12-methyl-4-oxo-6,9-dioxa-3,12-diazatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-18-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-16-methyl-4-oxo-6,9,12-trioxa-3,16-diazaoctadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(4-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)    pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-2-(2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;-   (2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide    and pharmaceutically acceptable salt thereof.

The compounds of Formula (I) may be in the form of a salt. Typically,the salts of the present invention are pharmaceutically acceptablesalts. Salts encompassed within the term “pharmaceutically acceptablesalts” refer to non-toxic salts of the compounds of this invention. Fora review on suitable salts see Berge et al, J. Pharm. Sci. 1977, 66,1-19.

Suitable pharmaceutically acceptable salts can include acid additionsalts. A pharmaceutically acceptable acid addition salt can be formed byreaction of a compound of formula (I) with a suitable inorganic ororganic acid (such as hydrobromic, hydrochloric, sulfuric, nitric,phosphoric, p-toluenesulfonic, benzenesulfonic, methanesulfonic,ethanesulfonic, naphthalenesulfonic such as 2-naphthalenesulfonic),optionally in a suitable solvent such as an organic solvent, to give thesalt which is usually isolated for example by crystallisation andfiltration. A pharmaceutically acceptable acid addition salt of acompound of formula (I) can comprise or be for example a hydrobromide,hydrochloride, sulfate, nitrate, phosphate, p-toluenesulfonate,benzenesulfonate, methanesulfonate, ethanesulfonate,naphthalenesulfonate (e.g. 2-naphthalenesulfonate) salt.

Other non-pharmaceutically acceptable salts, e.g. trifluoroacetates, maybe used, for example in the isolation of compounds of the invention, andare included within the scope of this invention.

The invention includes within its scope all possible stoichiometric andnon-stoichiometric forms of the compounds of formula (I).

While it is possible that, for use in therapy, the compound of theinvention may be administered as the raw chemical, it is possible topresent the active ingredient as a pharmaceutical composition.Accordingly, the invention further provides pharmaceutical compositionscomprising a compound of the invention and one or more pharmaceuticallyacceptable carriers, diluents, or excipients. The carrier(s),diluents(s) or excipient(s) must be acceptable in the sense of beingcompatible with the other ingredients of the composition and notdeleterious to the recipient thereof. In accordance with another aspectof the invention there is also provided a process for the preparation ofa pharmaceutical composition including the agent, or pharmaceuticallyacceptable salts thereof, with one or more pharmaceutically acceptablecarriers, diluents or excipients. The pharmaceutical composition can befor use in the treatment and/or prophylaxis of any of the conditionsdescribed herein.

Pharmaceutical compositions may be presented in unit dose formscontaining a predetermined amount of active ingredient per unit dose.Preferred unit dosage compositions are those containing a daily dose orsub-dose, or an appropriate fraction thereof, of an active ingredient.Such unit doses may therefore be administered once or more than once aday. Such pharmaceutical compositions may be prepared by any of themethods well known in the pharmacy art.

Pharmaceutical compositions may be adapted for administration by anyappropriate route, for example by the oral (including buccal orsublingual), rectal, inhaled, intranasal, topical (including buccal,sublingual or transdermal), vaginal or parenteral (includingsubcutaneous, intramuscular, intravenous or intradermal) route. Suchcompositions may be prepared by any method known in the art of pharmacy,for example by bringing into association the active ingredient with thecarrier(s) or excipient(s).

Pharmaceutical compositions adapted for oral administration may bepresented as discrete units such as capsules or tablets; powders orgranules; solutions or suspensions in aqueous or non-aqueous liquids;edible foams or whips; or oil-in-water liquid emulsions or water-in-oilliquid emulsions.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Powders are prepared by reducing thecompound to a suitable fine size and mixing with a similarly preparedpharmaceutical carrier such as an edible carbohydrate, as, for example,starch or mannitol. Flavouring, preservative, dispersing and colouringagent can also be present.

Capsules are made by preparing a powder mixture, as described above, andfilling formed gelatin sheaths. Glidants and lubricants such ascolloidal silica, talc, magnesium stearate, calcium stearate or solidpolyethylene glycol can be added to the powder mixture before thefilling operation. A disintegrating or solubilizing agent such asagar-agar, calcium carbonate or sodium carbonate can also be added toimprove the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, glidants,lubricants, sweetening agents, flavours, disintegrating agents andcolouring agents can also be incorporated into the mixture. Suitablebinders include starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonite,xanthan gum and the like. Tablets are formulated, for example, bypreparing a powder mixture, granulating or slugging, adding a lubricantand disintegrant and pressing into tablets. A powder mixture is preparedby mixing the compound, suitably comminuted, with a diluent or base asdescribed above, and optionally, with a binder such ascarboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone,a solution retardant such as paraffin, a resorption accelerator such asa quaternary salt and/or an absorption agent such as bentonite, kaolinor dicalcium phosphate. The powder mixture can be granulated by wettingwith a binder such as syrup, starch paste, acadia mucilage or solutionsof cellulosic or polymeric materials and forcing through a screen. As analternative to granulating, the powder mixture can be run through thetablet machine and the result is imperfectly formed slugs broken intogranules. The granules can be lubricated to prevent sticking to thetablet forming dies by means of the addition of stearic acid, a stearatesalt, talc or mineral oil. The lubricated mixture is then compressedinto tablets. The compounds of the present invention can also becombined with a free flowing inert carrier and compressed into tabletsdirectly without going through the granulating or slugging steps. Aclear or opaque protective coating consisting of a sealing coat ofshellac, a coating of sugar or polymeric material and a polish coatingof wax can be provided. Dyestuffs can be added to these coatings todistinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared indosage unit form so that a given quantity contains a predeterminedamount of the compound. Syrups can be prepared by dissolving thecompound in a suitably flavoured aqueous solution, while elixirs areprepared through the use of a non-toxic alcoholic vehicle. Suspensionscan be formulated by dispersing the compound in a non-toxic vehicle.Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols andpolyoxy ethylene sorbitol ethers, preservatives, flavor additive such aspeppermint oil or natural sweeteners or saccharin or other artificialsweeteners, and the like can also be added.

Where appropriate, dosage unit compositions for oral administration canbe microencapsulated. The composition can also be prepared to prolong orsustain the release as for example by coating or embedding particulatematerial in polymers, wax or the like.

The compounds of the invention may also be administered in the form ofliposome delivery systems, such as small unilamellar vesicles, largeunilamellar vesicles and multilamellar vesicles. Liposomes can be formedfrom a variety of phospholipids, such as cholesterol, stearylamine orphosphatidylcholines.

Pharmaceutical compositions adapted for transdermal administration maybe presented as discrete patches intended to remain in intimate contactwith the epidermis of the recipient for a prolonged period of time.

Pharmaceutical compositions adapted for topical administration may beformulated as ointments, creams, suspensions, lotions, powders,solutions, pastes, gels, sprays, aerosols or oils.

For treatments of the eye or other external tissues, for example mouthand skin, the compositions are preferably applied as a topical ointmentor cream. When formulated in an ointment, the active ingredient may beemployed with either a paraffinic or a water-miscible ointment base.Alternatively, the active ingredient may be formulated in a cream withan oil-in-water cream base or a water-in-oil base.

Pharmaceutical compositions adapted for topical administrations to theeye include eye drops wherein the active ingredient is dissolved orsuspended in a suitable carrier, especially an aqueous solvent.

Pharmaceutical compositions adapted for topical administration in themouth include lozenges, pastilles and mouth washes.

Pharmaceutical compositions adapted for rectal administration may bepresented as suppositories or as enemas.

Dosage forms for nasal or inhaled administration may conveniently beformulated as aerosols, solutions, suspensions drops, gels or drypowders.

Pharmaceutical compositions adapted for vaginal administration may bepresented as pessaries, tampons, creams, gels, pastes, foams or sprayformulations.

Pharmaceutical compositions adapted for parental administration includeaqueous and non-aqueous sterile injection solutions which may containanti-oxidants, buffers, bacteriostats and solutes which render thecomposition isotonic with the blood of the intended recipient; andaqueous and non-aqueous sterile suspensions which may include suspendingagents and thickening agents. The compositions may be presented inunit-dose or multi-dose containers, for example sealed ampoules andvials, and may be stored in a freeze-dried (lyophilized) conditionrequiring only the addition of the sterile liquid carrier, for examplewater for injections, immediately prior to use. Extemporaneous injectionsolutions and suspensions may be prepared from sterile powders, granulesand tablets.

It should be understood that in addition to the ingredients particularlymentioned above, the compositions may include other agents conventionalin the art having regard to the type of formulation in question, forexample those suitable for oral administration may include flavouringagents.

A therapeutically effective amount of the agent will depend upon anumber of factors including, for example, the age and weight of thesubject, the precise condition requiring treatment and its severity, thenature of the formulation, and the route of administration, and willultimately be at the discretion of the attendant physician orveterinarian. In particular, the subject to be treated is a mammal,particularly a human.

The agent may be administered in a daily dose. This amount may be givenin a single dose per day or in a number (such as two, three, four, fiveor six) of sub-doses per day such that the total daily dose is the same.

Suitably, the amount of the compound of the invention administeredaccording to the present invention will be an amount selected from 0.01mg to 1 g per day (calculated as the free or unsalted compound).

We have found that the compounds defined in the present invention, or apharmaceutically acceptable salt thereof, or pharmaceutical compositionscontaining them, are capable of degrading the estrogen-receptor.

Accordingly, the compounds of the present invention are expected to bepotentially useful agents in the treatment of diseases or medicalconditions mediated alone or in part by the estrogen receptor.

Provided herein are methods of treatment or prevention of diseases,disorders and conditions mediated by the estrogen receptor. A method maycomprise administering to a subject, e.g. a subject in need thereof, atherapeutically effective amount of a compound of the invention.

Thus in one aspect there is provided a compound of the invention for usein therapy

Thus in one aspect there is provided a compound of the invention for usein treating diseases, disorders or conditions mediated by the estrogenreceptor

Thus in one aspect there is provided the use of a compound of theinvention in the manufacture of a medicament for treating diseases,disorders or conditions mediated by the estrogen receptor.

In a further aspect there is provided a method of treatment of diseases,disorders or conditions mediated by the estrogen receptor in a mammalcomprising administering a therapeutically effective amount of acompound of the invention.

The compound of the invention are useful in the treatment of estrogenreceptor associated conditions. An “estrogen receptor-associatedcondition,” as used herein, denotes a condition or disorder which can betreated by modulating the function or activity of an estrogen receptorin a subject, wherein treatment comprises prevention, partialalleviation or cure of the condition or disorder. Modulation may occurlocally, for example, within certain tissues of the subject, or moreextensively throughout a subject being treated for such a condition ordisorder.

In one aspect the estrogen mediated disease or condition is breastcancer

The compounds of the present invention may be used in combination withor include one or more other therapeutic agents and may be administeredeither sequentially or simultaneously by any convenient route inseparate or combined pharmaceutical compositions.

The therapeutically effective amount of the further therapeutic agentsof the present invention will depend upon a number of factors including,for example, the age and weight of the mammal, the precise conditionrequiring treatment, the severity of the condition, the nature of theformulation, and the route of administration. Ultimately, thetherapeutically effective amount will be at the discretion of theattendant physician or veterinarian. The relative timings ofadministration will be selected in order to achieve the desired combinedtherapeutic effect.

The compounds of the present invention and further therapeutic agent(s)may be employed in combination by administration simultaneously in aunitary pharmaceutical composition including both compounds.Alternatively, the combination may be administered separately inseparate pharmaceutical compositions, each including one of thecompounds in a sequential manner wherein, for example, the compound ofthe invention is administered first and the other second and vice versa.Such sequential administration may be close in time (e.g.simultaneously) or remote in time. Furthermore, it does not matter ifthe compounds are administered in the same dosage form, e.g. onecompound may be administered topically and the other compound may beadministered orally. Suitably, both compounds are administered orally.

The combinations may be presented as a combination kit. By the term“combination kit” “or kit of parts” as used herein is meant thepharmaceutical composition or compositions that are used to administerthe combination according to the invention. When both compounds areadministered simultaneously, the combination kit can contain bothcompounds in a single pharmaceutical composition, such as a tablet, orin separate pharmaceutical compositions. When the compounds are notadministered simultaneously, the combination kit will contain eachcompound in separate pharmaceutical compositions either in a singlepackage or in separate pharmaceutical compositions in separate packages.

The combination kit can also be provided by instruction, such as dosageand administration instructions. Such dosage and administrationinstructions can be of the kind that are provided to a doctor, forexample by a drug product label, or they can be of the kind that areprovided by a doctor, such as instructions to a patient.

When the combination is administered separately in a sequential mannerwherein one is administered first and the other second or vice versa,such sequential administration may be close in time or remote in time.For example, administration of the other agent several minutes toseveral dozen minutes after the administration of the first agent, andadministration of the other agent several hours to several days afterthe administration of the first agent are included, wherein the lapse oftime is not limited, For example, one agent may be administered once aday, and the other agent may be administered 2 or 3 times a day, or oneagent may be administered once a week, and the other agent may beadministered once a day and the like.

It will be clear to a person skilled in the art that, where appropriate,the other therapeutic ingredients(s) may be used in the form of salts,for example as alkali metal or amine salts or as acid addition salts, orprodrugs, or as esters, for example lower alkyl esters, or as solvates,for example hydrates, to optimise the activity and/or stability and/orphysical characteristics, such as solubility, of the therapeuticingredient. It will be clear also that, where appropriate, thetherapeutic ingredients may be used in optically pure form.

When combined in the same composition it will be appreciated that thetwo compounds must be stable and compatible with each other and theother components of the composition and may be formulated foradministration. When formulated separately they may be provided in anyconvenient composition, conveniently, in such a manner as known for suchcompounds in the art.

When the compound of formula (I) is used in combination with a secondtherapeutic agent active against the same disease, condition ordisorder, the dose of each compound may differ from that when thecompound is used alone. Appropriate doses will be readily appreciated bythose skilled in the art.

In the embodiment, the compound of compound of formula (I) or apharmaceutically acceptable salt thereof may be employed with othertherapeutic methods of cancer treatment. In particular, inanti-neoplastic therapy, combination therapy with otherchemotherapeutic, hormonal, antibody agents as well as surgical and/orradiation treatments other than those mentioned above are envisaged.

As indicated, therapeutically effective amounts of the compound ofcompound of formula (I) or a pharmaceutically acceptable salt thereofare discussed above. The therapeutically effective amount of the furthertherapeutic agents of the present invention will depend upon a number offactors including, for example, the age and weight of the mammal, theprecise condition requiring treatment, the severity of the condition,the nature of the formulation, and the route of administration.Ultimately, the therapeutically effective amount will be at thediscretion of the attendant physician or veterinarian. The relativetimings of administration will be selected in order to achieve thedesired combined therapeutic effect.

In one embodiment, the further anti-cancer therapy is surgical and/orradiotherapy.

In one embodiment, the further anti-cancer therapy is at least oneadditional anti-neoplastic agent.

Any anti-neoplastic agent that has activity versus a susceptible tumorbeing treated may be utilized in the combination. Typicalanti-neoplastic agents useful include, but are not limited to,anti-microtubule agents such as diterpenoids and vinca alkaloids;platinum coordination complexes; alkylating agents such as nitrogenmustards, oxazaphosphorines, alkylsulfonates, nitrosoureas, andtriazenes; antibiotic agents such as anthracyclins, actinomycins andbleomycins; topoisomerase II inhibitors such as epipodophyllotoxins;antimetabolites such as purine and pyrimidine analogues and anti-folatecompounds; topoisomerase I inhibitors such as camptothecins; hormonesand hormonal analogues; signal transduction pathway inhibitors;non-receptor tyrosine angiogenesis inhibitors; immunotherapeutic agents;proapoptotic agents; and cell cycle signaling inhibitors.

Anti-Microtubule or Anti-Mitotic Agents:

Anti-microtubule or anti-mitotic agents are phase specific agents activeagainst the microtubules of tumor cells during M or the mitosis phase ofthe cell cycle. Examples of anti-microtubule agents include, but are notlimited to, diterpenoids and vinca alkaloids.

Diterpenoids, which are derived from natural sources, are phase specificanti-cancer agents that operate at the G₂/M phases of the cell cycle. Itis believed that the diterpenoids stabilize the β-tubulin subunit of themicrotubules, by binding with this protein. Disassembly of the proteinappears then to be inhibited with mitosis being arrested and cell deathfollowing. Examples of diterpenoids include, but are not limited to,paclitaxel and its analog docetaxel.

Paclitaxel, 5β,20-epoxy-1,2α,4,7β,10β,13α-hexa-hydroxytax-11-en-9-one4,10-diacetate 2-benzoate 13-ester with(2R,3S)—N-benzoyl-3-phenylisoserine; is a natural diterpene productisolated from the Pacific yew tree Taxus brevifolia and is commerciallyavailable as an injectable solution TAXOL®. It is a member of the taxanefamily of terpenes. Paclitaxel has been approved for clinical use in thetreatment of refractory ovarian cancer in the United States (Markman etal., Yale Journal of Biology and Medicine, 64:583, 1991; McGuire et al.,Ann. Intem, Med., 111:273, 1989) and for the treatment of breast cancer(Holmes et al., J. Nat. Cancer Inst., 83:1797, 1991.) It is a potentialcandidate for treatment of neoplasms in the skin (Einzig et. al., Proc.Am. Soc. Clin. Oncol., 20:46) and head and neck carcinomas (Forastireet. al., Sem. Oncol., 20:56, 1990). The compound also shows potentialfor the treatment of polycystic kidney disease (Woo et. al., Nature,368:750. 1994), lung cancer and malaria. Treatment of patients withpaclitaxel results in bone marrow suppression (multiple cell lineages,Ignoff, R. J. et. al, Cancer Chemotherapy Pocket Guide, 1998) related tothe duration of dosing above a threshold concentration (50 nM) (Kearns,C. M. et. al., Seminars in Oncology, 3(6) p. 16-23, 1995).

Docetaxel, (2R,3S)—N-carboxy-3-phenylisoserine,N-tert-butyl ester,13-ester with 5β-20-epoxy-1,2α,4,7β,10β,13α-hexahydroxytax-11-en-9-one4-acetate 2-benzoate, trihydrate; is commercially available as aninjectable solution as TAXOTERE®. Docetaxel is indicated for thetreatment of breast cancer. Docetaxel is a semisynthetic derivative ofpaclitaxel q.v., prepared using a natural precursor,10-deacetyl-baccatin III, extracted from the needle of the European Yewtree.

Vinca alkaloids are phase specific anti-neoplastic agents derived fromthe periwinkle plant. Vinca alkaloids act at the M phase (mitosis) ofthe cell cycle by binding specifically to tubulin. Consequently, thebound tubulin molecule is unable to polymerize into microtubules.Mitosis is believed to be arrested in metaphase with cell deathfollowing. Examples of vinca alkaloids include, but are not limited to,vinblastine, vincristine, and vinorelbine.

Vinblastine, vincaleukoblastine sulfate, is commercially available asVELBAN® as an injectable solution. Although, it has possible indicationas a second line therapy of various solid tumors, it is primarilyindicated in the treatment of testicular cancer and various lymphomasincluding Hodgkin's Disease; and lymphocytic and histiocytic lymphomas.Myelosuppression is the dose limiting side effect of vinblastine.

Vincristine, vincaleukoblastine, 22-oxo-, sulfate, is commerciallyavailable as ONCOVIN® as an injectable solution. Vincristine isindicated for the treatment of acute leukemias and has also found use intreatment regimens for Hodgkin's and non-Hodgkin's malignant lymphomas.Alopecia and neurologic effects are the most common side effect ofvincristine and to a lesser extent myelosupression and gastrointestinalmucositis effects occur.

Vinorelbine, 3′,4′-didehydro-4′-deoxy-C′-norvincaleukoblastine[R—(R*,R*)-2,3-dihydroxybutanedioate (1:2)(salt)], commerciallyavailable as an injectable solution of vinorelbine tartrate(NAVELBINE®), is a semisynthetic vinca alkaloid. Vinorelbine isindicated as a single agent or in combination with otherchemotherapeutic agents, such as cisplatin, in the treatment of varioussolid tumors, particularly non-small cell lung, advanced breast, andhormone refractory prostate cancers. Myelosuppression is the most commondose limiting side effect of vinorelbine.

Platinum Coordination Complexes:

Platinum coordination complexes are non-phase specific anti-canceragents, which are interactive with DNA. The platinum complexes entertumor cells, undergo, aquation and form intra- and interstrandcrosslinks with DNA causing adverse biological effects to the tumor.Examples of platinum coordination complexes include, but are not limitedto, oxaliplatin, cisplatin and carboplatin.

Cisplatin, cis-diamminedichloroplatinum, is commercially available asPLATINOL® as an injectable solution. Cisplatin is primarily indicated inthe treatment of metastatic testicular and ovarian cancer and advancedbladder cancer.

Carboplatin, platinum, diammine[1,1-cyclobutane-dicarboxylate(2-)-O,O′], is commercially available asPARAPLATIN® as an injectable solution. Carboplatin is primarilyindicated in the first and second line treatment of advanced ovariancarcinoma.

Alkylating Agents:

Alkylating agents are non-phase anti-cancer specific agents and strongelectrophiles. Typically, alkylating agents form covalent linkages, byalkylation, to DNA through nucleophilic moieties of the DNA moleculesuch as phosphate, amino, sulfhydryl, hydroxyl, carboxyl, and imidazolegroups. Such alkylation disrupts nucleic acid function leading to celldeath. Examples of alkylating agents include, but are not limited to,nitrogen mustards such as cyclophosphamide, melphalan, and chlorambucil;alkyl sulfonates such as busulfan; nitrosoureas such as carmustine; andtriazenes such as dacarbazine.

Cyclophosphamide,2-[bis(2-chloroethyl)amino]tetrahydro-2H-1,3,2-oxazaphosphorine 2-oxidemonohydrate, is commercially available as an injectable solution ortablets as CYTOXAN®. Cyclophosphamide is indicated as a single agent orin combination with other chemotherapeutic agents, in the treatment ofmalignant lymphomas, multiple myeloma, and leukemias.

Melphalan, 4-[bis(2-chloroethyl)amino]-L-phenylalanine, is commerciallyavailable as an injectable solution or tablets as ALKERAN®. Melphalan isindicated for the palliative treatment of multiple myeloma andnon-respectable epithelial carcinoma of the ovary. Bone marrowsuppression is the most common dose limiting side effect of melphalan.

Chlorambucil, 4-[bis(2-chloroethyl)amino]benzenebutanoic acid, iscommercially available as LEUKERAN® tablets. Chlorambucil is indicatedfor the palliative treatment of chronic lymphatic leukemia, andmalignant lymphomas such as lymphosarcoma, giant follicular lymphoma,and Hodgkin's disease.

Busulfan, 1,4-butanediol dimethanesulfonate, is commercially availableas MYLERAN® TABLETS. Busulfan is indicated for the palliative treatmentof chronic myelogenous leukemia.

Carmustine, 1,3-[bis(2-chloroethyl)-1-nitrosourea, is commerciallyavailable as single vials of lyophilized material as BiCNU®. Carmustineis indicated for the palliative treatment as a single agent or incombination with other agents for brain tumors, multiple myeloma,Hodgkin's disease, and non-Hodgkin's lymphomas.

Dacarbazine, 5-(3,3-dimethyl-1-triazeno)-imidazole-4-carboxamide, iscommercially available as single vials of material as DTIC-Dome®.Dacarbazine is indicated for the treatment of metastatic malignantmelanoma and in combination with other agents for the second linetreatment of Hodgkin's Disease.

Antibiotic Anti-Neoplastics:

Antibiotic anti-neoplastics are non-phase specific agents, which bind orintercalate with DNA. Typically, such action results in stable DNAcomplexes or strand breakage, which disrupts ordinary function of thenucleic acids leading to cell death. Examples of antibioticanti-neoplastic agents include, but are not limited to, actinomycinssuch as dactinomycin, anthrocyclins such as daunorubicin anddoxorubicin; and bleomycins.

Dactinomycin, also known as Actinomycin D, is commercially available ininjectable form as COSMEGEN®. Dactinomycin is indicated for thetreatment of Wilm's tumor and rhabdomyosarcoma.

Daunorubicin, (8S-cis-)-8-acetyl-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12naphthacenedione hydrochloride, is commercially available as a liposomalinjectable form as DAUNOXOME® or as an injectable as CERUBIDINE®.Daunorubicin is indicated for remission induction in the treatment ofacute nonlymphocytic leukemia and advanced HIV associated Kaposi'ssarcoma.

Doxorubicin,(8S,10S)-10-[(3-amino-2,3,6-trideoxy-α-L-lyxo-hexopyranosyl)oxy]-8-glycoloyl,7,8,9,10-tetrahydro-6,8,11-trihydroxy-1-methoxy-5,12 naphthacenedionehydrochloride, is commercially available as an injectable form as RUBEX®or ADRIAMYCIN RDF®. Doxorubicin is primarily indicated for the treatmentof acute lymphoblastic leukemia and acute myeloblastic leukemia, but isalso a useful component in the treatment of some solid tumors andlymphomas.

Bleomycin, a mixture of cytotoxic glycopeptide antibiotics isolated froma strain of Streptomyces verticillus, is commercially available asBLENOXANE®. Bleomycin is indicated as a palliative treatment, as asingle agent or in combination with other agents, of squamous cellcarcinoma, lymphomas, and testicular carcinomas.

Topoisomerase II Inhibitors:

Topoisomerase II inhibitors include, but are not limited to,epipodophyllotoxins.

Epipodophyllotoxins are phase specific anti-neoplastic agents derivedfrom the mandrake plant. Epipodophyllotoxins typically affect cells inthe S and G₂ phases of the cell cycle by forming a ternary complex withtopoisomerase II and DNA causing DNA strand breaks. The strand breaksaccumulate and cell death follows. Examples of epipodophyllotoxinsinclude, but are not limited to, etoposide and teniposide.

Etoposide, 4′-demethyl-epipodophyllotoxin9[4,6-0-(R)-ethylidene-β-D-glucopyranoside], is commercially availableas an injectable solution or capsules as VePESID® and is commonly knownas VP-16. Etoposide is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of testicular andnon-small cell lung cancers.

Teniposide, 4′-demethyl-epipodophyllotoxin 9[4,6-0-(R)-thenylidene-β-D-glucopyranoside], is commercially availableas an injectable solution as VUMON® and is commonly known as VM-26.Teniposide is indicated as a single agent or in combination with otherchemotherapy agents in the treatment of acute leukemia in children.

Antimetabolite Neoplastic Agents:

Antimetabolite neoplastic agents are phase specific anti-neoplasticagents that act at S phase (DNA synthesis) of the cell cycle byinhibiting DNA synthesis or by inhibiting purine or pyrimidine basesynthesis and thereby limiting DNA synthesis. Consequently, S phase doesnot proceed and cell death follows. Examples of antimetaboliteanti-neoplastic agents include, but are not limited to, fluorouracil,methotrexate, cytarabine, mecaptopurine, thioguanine, and gemcitabine.

5-fluorouracil, 5-fluoro-2,4-(1H,3H)pyrimidinedione, is commerciallyavailable as fluorouracil. Administration of 5-fluorouracil leads toinhibition of thymidylate synthesis and is also incorporated into bothRNA and DNA. The result typically is cell death. 5-fluorouracil isindicated as a single agent or in combination with other chemotherapyagents in the treatment of carcinomas of the breast, colon, rectum,stomach and pancreas. Other fluoropyrimidine analogs include 5-fluorodeoxyuridine (floxuridine) and 5-fluorodeoxyuridine monophosphate.

Cytarabine, 4-amino-1-β-D-arabinofuranosyl-2 (1H)-pyrimidinone, iscommercially available as CYTOSAR-U® and is commonly known as Ara-C. Itis believed that cytarabine exhibits cell phase specificity at S-phaseby inhibiting DNA chain elongation by terminal incorporation ofcytarabine into the growing DNA chain. Cytarabine is indicated as asingle agent or in combination with other chemotherapy agents in thetreatment of acute leukemia. Other cytidine analogs include5-azacytidine and 2′,2′-difluorodeoxycytidine (gemcitabine).

Mercaptopurine, 1,7-dihydro-6H-purine-6-thione monohydrate, iscommercially available as PURINETHOL®. Mercaptopurine exhibits cellphase specificity at S-phase by inhibiting DNA synthesis by an as of yetunspecified mechanism. Mercaptopurine is indicated as a single agent orin combination with other chemotherapy agents in the treatment of acuteleukemia. A useful mercaptopurine analog is azathioprine.

Thioguanine, 2-amino-1,7-dihydro-6H-purine-6-thione, is commerciallyavailable as TABLOID®. Thioguanine exhibits cell phase specificity atS-phase by inhibiting DNA synthesis by an as of yet unspecifiedmechanism. Thioguanine is indicated as a single agent or in combinationwith other chemotherapy agents in the treatment of acute leukemia. Otherpurine analogs include pentostatin, erythrohydroxynonyladenine,fludarabine phosphate, and cladribine.

Gemcitabine, 2′-deoxy-2′,2′-difluorocytidine monohydrochloride(β-isomer), is commercially available as GEMZAR®. Gemcitabine exhibitscell phase specificity at S-phase and by blocking progression of cellsthrough the G1/S boundary. Gemcitabine is indicated in combination withcisplatin in the treatment of locally advanced non-small cell lungcancer and alone in the treatment of locally advanced pancreatic cancer.

Methotrexate,N-[4[[(2,4-diamino-6-pteridinyl)methyl]methylamino]benzoyl]-L-glutamicacid, is commercially available as methotrexate sodium. Methotrexateexhibits cell phase effects specifically at S-phase by inhibiting DNAsynthesis, repair and/or replication through the inhibition ofdyhydrofolic acid reductase which is required for synthesis of purinenucleotides and thymidylate. Methotrexate is indicated as a single agentor in combination with other chemotherapy agents in the treatment ofchoriocarcinoma, meningeal leukemia, non-Hodgkin's lymphoma, andcarcinomas of the breast, head, neck, ovary and bladder.

Topoisomerase I Inhibitors:

Camptothecins, including, camptothecin and camptothecin derivatives areavailable or under development as Topoisomerase I inhibitors.Camptothecins cytotoxic activity is believed to be related to itsTopoisomerase I inhibitory activity. Examples of camptothecins include,but are not limited to irinotecan, topotecan, and the various opticalforms of7-(4-methylpiperazino-methylene)-10,11-ethylenedioxy-20-camptothecindescribed below.

Irinotecan HCl, (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino)carbonyloxy]-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride, is commercially available as the injectable solutionCAMPTOSAR®. Irinotecan is a derivative of camptothecin which binds,along with its active metabolite SN-38, to the topoisomerase I-DNAcomplex. It is believed that cytotoxicity occurs as a result ofirreparable double strand breaks caused by interaction of thetopoisomerase I:DNA:irintecan or SN-38 ternary complex with replicationenzymes. Irinotecan is indicated for treatment of metastatic cancer ofthe colon or rectum.

Topotecan HCl,(S)-10-[(dimethylamino)methyl]-4-ethyl-4,9-dihydroxy-1H-pyrano[3′,4′,6,7]indolizino[1,2-b]quinoline-3,14-(4H,12H)-dionemonohydrochloride, is commercially available as the injectable solutionHYCAMTIN®. Topotecan is a derivative of camptothecin which binds to thetopoisomerase I-DNA complex and prevents religation of singles strandbreaks caused by Topoisomerase I in response to torsional strain of theDNA molecule. Topotecan is indicated for second line treatment ofmetastatic carcinoma of the ovary and small cell lung cancer.

Hormones and Hormonal Analogues:

Hormones and hormonal analogues are useful compounds for treatingcancers in which there is a relationship between the hormone(s) andgrowth and/or lack of growth of the cancer. Examples of hormones andhormonal analogues useful in cancer treatment include, but are notlimited to, adrenocorticosteroids such as prednisone and prednisolonewhich are useful in the treatment of malignant lymphoma and acuteleukemia in children; aminoglutethimide and other aromatase inhibitorssuch as anastrozole, letrazole, vorazole, and exemestane useful in thetreatment of adrenocortical carcinoma and hormone dependent breastcarcinoma containing estrogen receptors; progestrins such as megestrolacetate useful in the treatment of hormone dependent breast cancer andendometrial carcinoma; estrogens, estrogens, and anti-estrogens such asfulvestrant, flutamide, nilutamide, bicalutamide, cyproterone acetateand 5α-reductases such as finasteride and dutasteride, useful in thetreatment of prostatic carcinoma and benign prostatic hypertrophy;anti-estrogens such as tamoxifen, toremifene, raloxifene, droloxifene,iodoxyfene, as well as selective estrogen receptor modulators (SERMS)such those described in U.S. Pat. Nos. 5,681,835, 5,877,219, and6,207,716, useful in the treatment of hormone dependent breast carcinomaand other susceptible cancers; and gonadotropin-releasing hormone (GnRH)and analogues thereof which stimulate the release of leutinizing hormone(LH) and/or follicle stimulating hormone (FSH) for the treatmentprostatic carcinoma, for instance, LHRH agonists and antagonists such asgoserelin acetate and luprolide.

Signal Transduction Pathway Inhibitors:

Signal transduction pathway inhibitors are those inhibitors, which blockor inhibit a chemical process which evokes an intracellular change. Asused herein this change is cell proliferation or differentiation. Signaltransduction inhibitors useful in the present invention includeinhibitors of receptor tyrosine kinases, non-receptor tyrosine kinases,SH2/SH3domain blockers, serine/threonine kinases, phosphotidylinositol-3 kinases, myo-inositol signaling, and Ras oncogenes.

Several protein tyrosine kinases catalyse the phosphorylation ofspecific tyrosyl residues in various proteins involved in the regulationof cell growth. Such protein tyrosine kinases can be broadly classifiedas receptor or non-receptor kinases.

Receptor tyrosine kinases are transmembrane proteins having anextracellular ligand binding domain, a transmembrane domain, and atyrosine kinase domain. Receptor tyrosine kinases are involved in theregulation of cell growth and are generally termed growth factorreceptors. Inappropriate or uncontrolled activation of many of thesekinases, i.e. aberrant kinase growth factor receptor activity, forexample by over-expression or mutation, has been shown to result inuncontrolled cell growth. Accordingly, the aberrant activity of suchkinases has been linked to malignant tissue growth. Consequently,inhibitors of such kinases could provide cancer treatment methods.Growth factor receptors include, for example, epidermal growth factorreceptor (EGFr), platelet derived growth factor receptor (PDGFr), erbB2,erbB4, ret, vascular endothelial growth factor receptor (VEGFr),tyrosine kinase with immunoglobulin-like and epidermal growth factorhomology domains (TIE-2), insulin growth factor-I (IGFI) receptor,macrophage colony stimulating factor (cfms), BTK, ckit, cmet, fibroblastgrowth factor (FGF) receptors, Trk receptors (TrkA, TrkB, and TrkC),ephrin (eph) receptors, and the RET protooncogene. Several inhibitors ofgrowth receptors are under development and include ligand antagonists,antibodies, tyrosine kinase inhibitors and anti-sense oligonucleotides.Growth factor receptors and agents that inhibit growth factor receptorfunction are described, for instance, in Kath, John C., Exp. Opin. Ther.Patents (2000) 10(6):803-818; Shawver et al DDT Vol 2, No. 2 Feb. 1997;and Lofts, F. J. et al, “Growth factor receptors as targets”, NewMolecular Targets for Cancer Chemotherapy, ed. Workman, Paul and Kerr,David, CRC press 1994, London.

Tyrosine kinases, which are not growth factor receptor kinases aretermed non-receptor tyrosine kinases. Non-receptor tyrosine kinasesuseful in the present invention, which are targets or potential targetsof anti-cancer drugs, include cSrc, Lck, Fyn, Yes, Jak, cAbl, FAK (Focaladhesion kinase), Brutons tyrosine kinase, and Bcr-Abl. Suchnon-receptor kinases and agents which inhibit non-receptor tyrosinekinase function are described in Sinh, S. and Corey, S. J., (1999)Journal of Hematotherapy and Stem Cell Research 8 (5): 465-80; andBolen, J. B., Brugge, J. S., (1997) Annual review of Immunology. 15:371-404. SH2/SH3 domain blockers are agents that disrupt SH2 or SH3domain binding in a variety of enzymes or adaptor proteins including,PI3-K p85 subunit, Src family kinases, adaptor molecules (Shc, Crk, Nck,Grb2) and Ras-GAP. SH2/SH3 domains as targets for anti-cancer drugs arediscussed in Smithgall, T. E. (1995), Journal of Pharmacological andToxicological Methods. 34(3) 125-32.

Inhibitors of Serine/Threonine Kinases including MAP kinase cascadeblockers which include blockers of Raf kinases (rafk), Mitogen orExtracellular Regulated Kinase (MEKs), and Extracellular RegulatedKinases (ERKs); and Protein kinase C family member blockers includingblockers of PKCs (alpha, beta, gamma, epsilon, mu, lambda, iota, zeta).IkB kinase family (IKKa, IKKb), PKB family kinases, akt kinase familymembers, and TGF beta receptor kinases. Such Serine/Threonine kinasesand inhibitors thereof are described in Yamamoto, T., Taya, S.,Kaibuchi, K., (1999), Journal of Biochemistry. 126 (5) 799-803; Brodt,P, Samani, A., and Navab, R. (2000), Biochemical Pharmacology, 60.1101-1107; Massague, J., Weis-Garcia, F. (1996) Cancer Surveys.27:41-64; Philip, P. A., and Harris, A. L. (1995), Cancer Treatment andResearch. 78: 3-27, Lackey, K. et al Bioorganic and Medicinal ChemistryLetters, (10), 2000, 223-226; U.S. Pat. No. 6,268,391; andMartinez-Iacaci, L., et al, Int. J. Cancer (2000), 88(1), 44-52.

Inhibitors of Phosphotidyl inositol-3 Kinase family members includingblockers of PI3-kinase, ATM, DNA-PK, and Ku are also useful in thepresent invention. Such kinases are discussed in Abraham, R. T. (1996),Current Opinion in Immunology. 8 (3) 412-8; Canman, C. E., Lim, D. S.(1998), Oncogene 17 (25) 3301-3308; Jackson, S. P. (1997), InternationalJournal of Biochemistry and Cell Biology. 29 (7):935-8; and Zhong, H. etal, Cancer res, (2000) 60(6), 1541-1545.

Also useful in the present invention are Myo-inositol signalinginhibitors such as phospholipase C blockers and Myoinositol analogues.Such signal inhibitors are described in Powis, G., and Kozikowski A.,(1994) New Molecular Targets for Cancer Chemotherapy ed., Paul Workmanand David Kerr, CRC press 1994, London.

Another group of signal transduction pathway inhibitors are inhibitorsof Ras Oncogene. Such inhibitors include inhibitors offarnesyltransferase, geranyl-geranyl transferase, and CAAX proteases aswell as anti-sense oligonucleotides, ribozymes and immunotherapy. Suchinhibitors have been shown to block ras activation in cells containingwild type mutant ras, thereby acting as antiproliferation agents. Rasoncogene inhibition is discussed in Scharovsky, O. G., Rozados, V. R.,Gervasoni, S. I. Matar, P. (2000), Journal of Biomedical Science. 7(4)292-8; Ashby, M. N. (1998), Current Opinion in Lipidology. 9 (2) 99-102;and BioChim. Biophys. Acta, (19899) 1423(3):19-30.

As mentioned above, antibody antagonists to receptor kinase ligandbinding may also serve as signal transduction inhibitors. This group ofsignal transduction pathway inhibitors includes the use of humanizedantibodies to the extracellular ligand binding domain of receptortyrosine kinases. For example Imclone C225 EGFR specific antibody (seeGreen, M. C. et al, Monoclonal Antibody Therapy for Solid Tumors, CancerTreat. Rev., (2000), 26(4), 269-286); Herceptin® erbB2 antibody (seeTyrosine Kinase Signalling in Breast cancer:erbB Family ReceptorTyrosine Kinases, Breast cancer Res., 2000, 2(3), 176-183); and 2CBVEGFR2 specific antibody (see Brekken, R. A. et al, Selective Inhibitionof VEGFR2 Activity by a monoclonal Anti-VEGF antibody blocks tumorgrowth in mice, Cancer Res. (2000) 60, 5117-5124).

Anti-Angiogenic Agents:

(i) Anti-angiogenic agents including non-receptor MEK angiogenesisinhibitors may also be useful. Anti-angiogenic agents such as thosewhich inhibit the effects of vascular endothelial growth factor, (forexample the anti-vascular endothelial cell growth factor antibodybevacizumab [Avastin™], and compounds that work by other mechanisms (forexample linomide, inhibitors of integrin αvβ3 function, endostatin andangiostatin);Immunotherapeutic Agents:

Agents used in immunotherapeutic regimens may also be useful incombination with the compounds of formula (I). Immunotherapy approaches,including for example ex-vivo and in-vivo approaches to increase theimmunogenicity of patient tumour cells, such as transfection withcytokines such as interleukin 2, interleukin 4 or granulocyte-macrophagecolony stimulating factor, approaches to decrease T-cell anergy,approaches using transfected immune cells such as cytokine-transfecteddendritic cells, approaches using cytokine-transfected tumour cell linesand approaches using anti-idiotypic antibodies

Proapoptotic Agents:

Agents used in proapoptotic regimens (e.g., bcl-2 antisenseoligonucleotides) may also be used in the combination of the presentinvention.

Cell Cycle Signalling Inhibitors

Cell cycle signalling inhibitors inhibit molecules involved in thecontrol of the cell cycle. A family of protein kinases called cyclindependent kinases (CDKs) and their interaction with a family of proteinstermed cyclins controls progression through the eukaryotic cell cycle.The coordinate activation and inactivation of different cyclin/CDKcomplexes is necessary for normal progression through the cell cycle.Several inhibitors of cell cycle signalling are under development. Forinstance, examples of cyclin dependent kinases, including CDK2, CDK4,and CDK6 and inhibitors for the same are described in, for instance,Rosania et al, Exp. Opin. Ther. Patents (2000) 10(2):215-230.

In one embodiment, the combination of the present invention comprises acompound of formula I or a salt or solvate thereof and at least oneanti-neoplastic agent selected from anti-microtubule agents, platinumcoordination complexes, alkylating agents, antibiotic agents,topoisomerase II inhibitors, antimetabolites, topoisomerase Iinhibitors, hormones and hormonal analogues, signal transduction pathwayinhibitors, non-receptor tyrosine MEK angiogenesis inhibitors,immunotherapeutic agents, proapoptotic agents, and cell cycle signalinginhibitors.

In one embodiment, the combination of the present invention comprises acompound of formula I or a salt or solvate thereof and at least oneanti-neoplastic agent which is an anti-microtubule agent selected fromditerpenoids and vinca alkaloids.

In a further embodiment, at least one anti-neoplastic agent is aditerpenoid.

In a further embodiment, at least one anti-neoplastic agent is a vincaalkaloid.

In one embodiment, the combination of the present invention comprises acompound of formula I or a salt or solvate thereof and at least oneanti-neoplastic agent, which is a platinum coordination complex.

In a further embodiment, at least one anti-neoplastic agent ispaclitaxel, carboplatin, or vinorelbine.

In a further embodiment, at least one anti-neoplastic agent iscarboplatin.

In a further embodiment, at least one anti-neoplastic agent isvinorelbine.

In a further embodiment, at least one anti-neoplastic agent ispaclitaxel.

In one embodiment, the combination of the present invention comprises acompound of formula I and salts or solvates thereof and at least oneanti-neoplastic agent which is a signal transduction pathway inhibitor.

In a further embodiment the signal transduction pathway inhibitor is aninhibitor of a growth factor receptor kinase VEGFR2, TIE2, PDGFR, BTK,erbB2, EGFr, IGFR-1, TrkA, TrkB, TrkC, or c-fms.

In a further embodiment the signal transduction pathway inhibitor is aninhibitor of a serine/threonine kinase rafk, akt, or PKC-zeta.

In a further embodiment the signal transduction pathway inhibitor is aninhibitor of a non-receptor tyrosine kinase selected from the src familyof kinases.

In a further embodiment the signal transduction pathway inhibitor is aninhibitor of c-src.

In a further embodiment the signal transduction pathway inhibitor is aninhibitor of Ras oncogene selected from inhibitors of farnesyltransferase and geranylgeranyl transferase.

In a further embodiment the signal transduction pathway inhibitor is aninhibitor of a serine/threonine kinase selected from the groupconsisting of PI3K.

In a further embodiment the signal transduction pathway inhibitor is adual EGFr/erbB2 inhibitor, for exampleN-{3-Chloro-4-[(3-fluorobenzyl)oxy]phenyl}-6-[5-({[2-(methanesulphonyl)ethyl]amino}methyl)-2-furyl]-4-quinazolinamine(structure below):

In one embodiment, the combination of the present invention comprises acompound of formula I or a salt or solvate thereof and at least oneanti-neoplastic agent which is a cell cycle signaling inhibitor.

In further embodiment, cell cycle signaling inhibitor is an inhibitor ofCDK2, CDK4 or CDK6.

Particular components of combination therapy include combinations withother anti-estrogens including tamoxifen and/or fulvestrant.

In one embodiment the mammal in the methods and uses of the presentinvention is a human.

General Synthetic Methods

Compounds of general formula (I) may be prepared by methods known in theart of organic synthesis as set forth in the specific Examples describedbelow. In all of the methods, it is well understood that protectinggroups for sensitive or reactive groups may be employed where necessaryin accordance with general principles of chemistry. Protecting groupsare manipulated according to standard methods of organic synthesis (T.W. Green and P. G. M. Wuts (1999) Protective Groups in OrganicSynthesis, 3^(rd) edition, John Wiley & Sons). These groups are removedat a convenient stage of the compound synthesis using methods that arereadily apparent to those skilled in the art. The selection of processesas well as the reaction conditions and order of their execution shall beconsistent with the preparation of compounds of Formula (I).

EXPERIMENTAL

Abbreviations

-   DCM: dichloromethane.-   DIPEA: N,N-diisopropylethylamine.-   DMF: N,N-dimethylformamide.-   h: hour.-   HATU: 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate.-   HPLC: high-performance liquid chromatography.-   LCMS: liquid chromatography-mass spectrometry-   Min: minutes.-   NMR: Nuclear magnetic resonance.-   RT: retention time.-   tBu: tert-butoxide.-   TFA: trifluoroacetic acid.-   THF: tetrahydrofuran.-   TMSCl: trimethylsilyl chloride.    LCMS Method:

The analysis was conducted on an Acquity UPLC BEH C18 column (50 mm×2.1mm internal diameter 1.7 μm packing diameter) at 40° C.

The solvents employed were:

A=0.1% v/v solution of formic acid in water.

B=0.1% v/v solution of formic acid in acetonitrile.

The gradient employed was as follows:

Time Flow Rate (minutes) (mL/min) % A % B 0 1 97 3 1.5 1 0 100 1.9 1 0100 2.0 1 97 3

The UV detection was an averaged signal from wavelength of 210 nm to 350nm and mass spectra were recorded on a mass spectrometer usingalternate-scan positive and negative mode electrospray ionization.

The following illustrates the mobile phases and gradients used whencompounds underwent purification by mass-directed autopreparative HPLC.

Mass-Directed Autopreparative HPLC (Formic Acid Modifier)

The HPLC analysis was conducted on a Sunfire C18 column (150 mm×30 mminternal diameter, 5 μm packing diameter) at ambient temperature.

The solvents employed were:

A=0.1% v/v solution of formic acid in water.

B=0.1% v/v solution of formic acid in acetonitrile.

Mass-Directed Autopreparative HPLC (Ammonium Bicarbonate Modifier)

The HPLC analysis was conducted on an XBridge C18 column (150 mm×30 mminternal diameter, 5 μm packing diameter) at ambient temperature.

The solvents employed were:

A=10 mM ammonium bicarbonate in water adjusted to pH 10 with ammoniasolution.

B=acetonitrile.

For each of the mass-directed autopreparative purifications,irrespective of the modifier used, the gradient employed was dependentupon the retention time of the particular compound undergoingpurification as recorded in the analytical LCMS, and was as follows:

For compounds with an analytical LCMS retention time below 0.6 minutesthe following gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 99 1 1 40 99 1 10 40 7030 11 40 1 99 15 40 1 99

For compounds with an analytical LCMS retention time between 0.6 and 0.9minutes the following gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 85 15 1 40 85 15 10 40 4555 11 40 1 99 15 40 1 99

For compounds with an analytical LCMS retention time between 0.9 and 1.2minutes the following gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 70 30 1 40 70 30 10 40 1585 11 40 1 99 15 40 1 99

For compounds with an analytical LCMS retention time between 1.2 and 1.4minutes the following gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 50 50 1 40 50 50 10 40 199 11 40 1 99 15 40 1 99

For compounds with an analytical LCMS retention time greater than 1.4minutes (LCMS method A) or greater than 3.6 minutes (LCMS method B) thefollowing gradient was used:

Time Flow Rate (minutes) (mL/min) % A % B 0 40 20 80 1 40 20 80 10 40 199 11 40 1 99 15 40 1 99

The UV detection was an averaged signal from wavelength of 210 nm to 350nm and mass spectra were recorded on a mass spectrometer usingalternate-scan positive and negative mode electrospray ionization.

The chemical names were generated using ACD Name Pro version 6.02 fromAdvanced Chemistry Development, Inc.

4-((6-Methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenol can beprepared according to the process described by Palkowitz, Alan David,U.S. Pat. No. 5,492,922A.

3-Bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene 1-oxide can beprepared according to the process described by Zhihui Qin et al. J. Med.Chem. 2007, 50, 2682-2692.

3-Bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene 1-oxide can beprepared according to the process described by Hong Liu et al. Chem.Res. Toxicol. 2005, 18, 162-173.

tert-Butyl 2-(2-(benzyloxy)ethoxy)acetate

KO^(t)Bu (3.24 g, 29 mmol) was added to a stirred solution of2-(benzyloxy)ethanol (commercially available from for example Aldrich)(4 g, 26 mmol) in tBuOH (30 mL) and the mixture was stirred at roomtemperature for 2 hours. Tert-butyl 2-bromoacetate (commerciallyavailable from for example Aldrich) (7 mL, 47 mmol) was then added, andthe mixture was stirred at room temperature overnight. The mixture wasdiluted with DCM (50 mL) and washed with water (2×50 mL) and then brine(2×50 mL). The organic extract was dried using a hydrophobic frit andconcentrated under reduced pressure. The crude product was purified bychromatography on silica (330 g cartridge) using a gradient elution from0% to 100% methyl tert-butyl ether in cyclohexane to afford the titlecompound (724 mg, 2.3 mmol, 9% yield). LCMS RT=1.10 min, ES+ve m/z 267.4[M+H]⁺

tert-Butyl 2-(2-hydroxyethoxy)acetate

A mixture of tert-butyl 2-(2-(benzyloxy)ethoxy)acetate (724 mg, 2.3mmol) and 10% w/w palladium on carbon (365 mg, 0.34 mmol) in ethanol (10mL) was stirred at room temperature under an atmosphere of hydrogen for1.5 hours. The palladium on carbon was filtered through celite and thefiltrate evaporated under reduced pressure to afford the title compound(349 mg, 1.8 mmol, 78% yield). LCMS RT=0.61 min, ES+ve m/z 263.4 [M+H]⁺.

tert-Butyl 2-(2-(tosyloxy)ethoxy)acetate

Tosyl chloride (578 mg, 3.0 mmol) was added to a cooled solution (0° C.)of tert-butyl 2-(2-hydroxyethoxy)acetate (349 mg, 1.8 mmol) in pyridine(4 mL). The reaction was stirred at room temperature for 16 hours. Thereaction mixture was partitioned between ethyl acetate (50 mL) and 2Maqueous HCl (40 mL). The organic extract was separated, washed with 2Maqueous HCl (40 mL), followed by saturated sodium bicarbonate (50 mL)and brine (50 mL). The organic extract was then dried (hydrophobic frit)and concentrated under reduced pressure to afford the title compound(618 mg, 1.50 mmol, 84% yield). LCMS RT=1.14 min, ES+ve m/z 348.0[M+NH₄]⁺.

tert-Butyl 2-(2-(2-(benzyloxy)ethoxy)ethoxy)acetate

KO^(t)Bu (20 mL, 20 mmol) was added to a stirred solution of2-(2-(benzyloxy)ethoxy)ethanol (commercially available from for exampleAldrich) (2.74 mL, 15 mmol) in tBuOH (30 mL) and the mixture was stirredunder a nitrogen atmosphere at room temperature for 2 hours. Thereaction mixture was cooled to 0° C., tert-butyl 2-bromoacetate(commercially available from for example Aldrich) (4 mL, 28 mmol) wasadded and the mixture stirred at room temperature overnight. Thereaction mixture was then concentrated, and partitioned between water(50 mL) and DCM (50 mL). The organic layer was separated and the aqueouslayer was extracted further with DCM (50 mL). The combined organiclayers were dried using a hydrophobic frit and concentrated underreduced pressure. The product was purified by chromatography on silicausing a gradient elution from 0% to 100% methyl tert-butyl ether incyclohexane to afford the title compound (3.56 g, 11 mmol, 74% yield).LCMS RT=1.11 min, ES+ve m/z 311.4 [M+H]⁺, 328.4 [M+NH₄]⁺.

tert-Butyl 2-(2-(2-hydroxyethoxy)ethoxy)acetate

A mixture of tert-butyl 2-(2-(2-(benzyloxy)ethoxy)ethoxy)acetate (7.97g, 25 mmol) and 10% w/w palladium on carbon (2.68 g, 2.5 mmol) inethanol (100 mL) was stirred at room temperature under an atmosphere ofhydrogen for 1.5 hours. The mixture was filtered through celite and thefiltrate evaporated under reduced pressure to afford the title compound(5.45 g, 22 mmol, 88% yield). LCMS RT=0.65 min, ES+ve m/z 238.1[M+NH₄]⁺. ¹H NMR (400 MHz, CDCl₃) δ=3.98 (s, 2H), 3.74-3.64 (m, 6H),3.62-3.55 (m, 2H), 2.77 (t, J=6.0 Hz, 1H), 1.44 (s, 9H).

tert-Butyl 2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate

Tosyl chloride (commercially available from for example Aldrich) (3.60g, 19 mmol) was added to a cooled solution (0° C.) of tert-butyl2-(2-(2-hydroxyethoxy)ethoxy)acetate (2.72 g, 11 mmol) in pyridine (25mL). The reaction was slowly warmed to room temperature and stirred for16 hours. The reaction mixture was partitioned between ethyl acetate (30mL) and 2M aqueous HCl (30 mL). The organic extract was separated,washed with 2M aqueous HCl (30 mL), dried using a hydrophobic frit, andconcentrated under reduced pressure. The product was purified bychromatography on silica (330 g cartridge) using a gradient elution from0% to 100% methyl tert-butyl ether in cyclohexane to afford the titlecompound (1.71 g, 4.5 mmol, 40% yield). LCMS RT=1.13 min, ES+ve m/z375.3 [M+H]⁺.

tert-Butyl 1-phenyl-2,5,8,11-tetraoxatridecan-13-oate

Potassium tert-butoxide (commercially available from for exampleAldrich) (7.71 g, 69 mmol) was added to a stirred solution of2-(2-(2-(benzyloxy)ethoxy)ethoxy)ethanol (commercially available fromfor example Fluorochem) (15 g, 62 mmol) in tert-butanol (200 mL) and thereaction mixture was stirred at room temperature for 2 h. The reactionmixture was cooled to 0° C., tert-butyl 2-bromoacetate (commerciallyavailable from for example Aldrich) (17 mL, 112 mmol) was added, and themixture was stirred at room temperature overnight. DCM (300 mL) wasadded and the organic phase was washed with water (300 mL) and thenbrine (2×200 mL). The organic extract was dried using a hydrophobic fritand concentrated under reduced pressure to give the crude product as ayellow oil. The product was purified by chromatography on silica using agradient elution from 0% to 100% methyl tert-butyl ether in cyclohexaneto afford the title compound (13.3 g, 38 mmol, 60% yield). LCMS RT=1.10min, ES+ve m/z 372.4 [M+NH₄]⁺.

tert-Butyl 2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate

A mixture of tert-butyl 1-phenyl-2,5,8,11-tetraoxatridecan-13-oate (13.3g, 38 mmol) and palladium on carbon (10% w/w, 11.4 g, 11 mmol) inethanol (200 mL) was stirred at room temperature under an atmosphere ofhydrogen for 1.5 h. The mixture was filtered through celite and thefiltrate was evaporated under reduced pressure to afford the titlecompound (9.74 g, 37 mmol, 98% yield) as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ=4.54 (s, 1H), 3.99 (s, 2H), 3.60-3.40 (m, 12H), 1.43 (s, 9H).

tert-Butyl 2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate

Tosyl chloride (commercially available from for example Aldrich) (11.9g, 63 mmol) was added to a cooled solution (0° C.) of tert-butyl2-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)acetate (9.74 g, 37 mmol) inpyridine (150 mL). The reaction was stirred at room temperature for 16h. The reaction mixture was partitioned between ethyl acetate (300 mL)and aqueous HCl (2M, 300 mL). The organic extract was washed withfurther aqueous HCl (2M, 300 mL), saturated K₂CO₃ (100 mL) and brine(100 mL). The organic extract was dried using MgSO₄ and concentratedunder reduced pressure to afford the title compound (10.3 g, 25 mmol,67% yield) as a yellow oil. LCMS RT=1.14 min, ES+ve 436.2 [M+NH₄]⁺.

2-(2-(3-(Benzyloxy)propoxy)ethoxy)ethanol

Sodium hydride (60% w/w in mineral oil) (350 mg, 8.8 mmol) was added toa mixture of 2,2′-oxydiethanol (commercially available from for exampleAldrich) (2.32 g, 22 mmol) and ((3-bromopropoxy)methyl)benzene(commercially available from for example Aldrich) (0.77 mL, 4.4 mmol) inDMF (10 mL). The reaction mixture was stirred at room temperature for 3hours. An additional aliquot of sodium hydride, (60% w/w in mineral oil)(350 mg, 8.8 mmol) was added and the reaction mixture was stirred atroom temperature for 16 hours. The mixture was partitioned between ethylacetate (50 mL) and water (50 mL). The organic layer was separated,dried using a hydrophobic frit and concentrated under reduced pressure.The product was purified by chromatography on silica (50 g cartridge)using a gradient elution from 0% to 25% MeOH in DCM to afford the titlecompound (648 mg, 2.6 mmol, 58% yield). LCMS RT=0.78 min, ES+ve m/z255.1 [M+H]⁺

tert-Butyl 1-phenyl-2,6,9,12-tetraoxatetradecan-14-oate

KO^(t)Bu (315 mg, 2.8 mmol) was added to a stirred solution of2-(2-(3-(benzyloxy)propoxy)ethoxy)ethanol (648 mg, 2.6 mmol) in tBuOH (8mL) and the mixture was stirred at room temperature for 2 hours.Tert-butyl 2-bromoacetate (commercially available from for exampleAldrich) (0.68 mL, 4.6 mmol) was added, and the mixture was stirred atroom temperature overnight. Further aliquots of KO^(t)Bu (315 mg, 2.8mmol) and tert-butyl 2-bromoacetate (0.68 mL, 4.6 mmol) were added andthe reaction was stirred at room temperature for 6 hours. A finalaliquot of tert-butyl 2-bromoacetate (0.68 mL, 4.6 mmol) was added andthe reaction was stirred for 16 hours. The reaction mixture waspartitioned between water (50 mL) and DCM (70 mL). The organic layer wasseparated, dried using a hydrophobic frit and concentrated under reducedpressure. The product was purified by chromatography on silica using agradient elution from 0% to 100% methyl tert-butyl ether in cyclohexane,followed by 0% to 20% MeOH in cyclohexane to afford the title compound(438 mg, 1.2 mmol, 47% yield). LCMS RT=1.16 min, ES+ve m/z 369.5 [M+H]⁺

tert-Butyl 2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)acetate

A mixture of tert-butyl 1-phenyl-2,6,9,12-tetraoxatetradecan-14-oate(418 mg, 1.13 mmol) and 10% w/w palladium on carbon (0.05 g, 0.47 mmol)in ethanol (5 mL) was stirred under an atmosphere of hydrogen for 2hours. The mixture was filtered through celite and the filtrateevaporated under reduced pressure to afford the title compound (314 mg,1.1 mmol, 99% yield). ¹H NMR (400 MHz, CDCl₃) δ=4.03 (s, 2H), 3.84-3.75(m, 2H), 3.74-3.58 (m, 10H), 2.58-2.43 (m, 1H), 1.87-1.78 (m, 2H), 1.48(s, 9H).

tert-Butyl 2-(2-(2-(3-(tosyloxy)propoxy)ethoxy)ethoxy)acetate

Tosyl chloride (commercially available from for example Aldrich) (430mg, 2.3 mmol) was added to a cooled solution (0° C.) of tert-butyl2-(2-(2-(3-hydroxypropoxy)ethoxy)ethoxy)acetate (314 mg, 1.1 mmol) inpyridine (5 mL). The reaction was slowly warmed to room temperature andstirred for 16 hours. The reaction mixture was partitioned between ethylacetate (30 mL) and saturated aqueous sodium bicarbonate (30 mL). Theorganic extract was washed with additional saturated aqueous sodiumbicarbonate (2×30 mL), brine (30 mL), dried using a hydrophobic frit andconcentrated under reduced pressure. The crude product was purified bychromatography on silica using a gradient elution from 0% to 100% methyltert-butyl ether in cyclohexane to afford the title compound (310 mg,0.72 mmol, 64% yield). LCMS RT=1.14 min, ES+ve m/z 450.3 [M+NH₄]⁺.

(2S,4R)-tert-Butyl2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate

An ice-cooled mixture of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(commercially available from for example Aldrich) (7.95 g, 34 mmol) and(4-bromophenyl)methanamine (commercially available from for exampleFluroChem) (6.4 g, 34 mmol) in DMF (200 mL) was treated with DIPEA (18mL, 103 mmol) and then with HATU (14.4 g, 38 mmol) and the mixture wasstirred at ambient temperature for 30 minutes. The reaction was quenchedwith water (200 mL) and extracted with ethyl acetate (2×200 mL). Thecombined organic layers were washed with saturated aqueous sodiumbicarbonate (2×300 mL), water (100 mL), brine (200 mL), dried overmagnesium sulphate and evaporated to dryness. The product was purifiedby chromatography on silica using a gradient elution from 0% to 10%methanol in DCM to afford the title compound (12.9 g, 32 mmol, 94%yield). LCMS RT=0.87 min, ES+ve m/z 399.2/401.2 [M+H]⁺.

(2S,4R)-tert-Butyl4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate

A mixture of (2S,4R)-tert-butyl2-((4-bromobenzyl)carbamoyl)-4-hydroxypyrrolidine-1-carboxylate (12.9 g,32 mmol), 4-methylthiazole (commercially available from for exampleAldrich) (5.9 mL, 65 mmol), palladium(II) acetate (commerciallyavailable from for example Aldrich) (0.145 g, 0.65 mmol) and potassiumacetate (6.34 g, 65 mmol) in N-methyl-2-pyrrolidone (80 mL) was stirredat 120° C. under nitrogen for 18 hours. Water (100 ml) was added and theproduct was extracted with ethyl acetate (4×300 mL). The combinedorganic phase was washed with brine (5×200 mL), dried over magnesiumsulfate and evaporated to dryness. The product was purified bychromatography on silica using a gradient elution from 0% to 10%methanol in DCM to afford the title compound (8 g, 19 mmol, 59% yield).LCMS RT=0.75 min, ES+ve m/z 418.4 [M+H]⁺.

(2S,4R)-4-Hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride

(2S,4R)-tert-Butyl4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate(8 g, 19 mmol) was dissolved in methanol (30 mL) and DCM (20 mL) andtreated with HCl in dioxane (4M, 8 mL, 32 mmol). The reaction mixturewas stirred at ambient temperature for 2 hours. The solvent was removedunder reduced pressure and the residue was triturated with DCM, filteredand dried under reduced pressure to afford the title compound (6.7 g, 19mmol, 99% yield). LCMS RT=0.49 min, ES+ve m/z 318.3 [M+H]⁺.

tert-Butyl((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate

A stirred mixture of(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (125 mg, 0.35 mmol) and(S)-2-((tert-butoxycarbonyl)amino)-3-methylbutanoic acid (commerciallyavailable from for example Aldrich) (77 mg, 0.35 mmol) in DMF (0.9 mL)was treated with DIPEA (0.22 mL, 1.3 mmol) and then with HATU (134 mg,0.35 mmol) and the mixture was stirred at ambient temperature for 1hour. The reaction mixture was subjected directly to purification bymass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (120 mg, 0.23 mmol, 72% yield). LCMS RT=0.87min, ES+ve m/z 517.3 [M+H]⁺.

(2S,4R)-1-((S)-2-Amino-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride

A solution of tert-butyl((S)-1-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)carbamate(287 mg, 0.56 mmol) in THF (5 mL) was treated with HCl in 1,4-dioxan(4M, 10 mL, 40 mmol) and stirred at ambient temperature for 2 hours. Themixture was evaporated to dryness to afford the title compound (224 mg,0.49 mmol, quantitative). LCMS RT=0.55 min, ES+ve m/z 417.3 [M+H]⁺.

tert-Butyl((S)-1-cyclopentyl-2-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate

HATU (260 mg, 0.68 mmol) was added to a solution of(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (200 mg, 0.57 mmol),(S)-2-((tert-butoxycarbonyl)amino)-2-cyclopentylacetic acid(commercially available from for example Fluorochem) (180 mg, 0.74 mmol)and DIPEA (0.40 mL, 2.3 mmol) in DMF (2 mL). The reaction was stirred atroom temperature for 30 min, and was subjected directly to purificationby mass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (200 mg, 0.37 mmol, 65% yield). LCMS RT=0.94min, ES+ve m/z 543.4 [M+H]⁺.

(2S,4R)-1-((S)-2-Amino-2-cyclopentylacetyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride

A solution of tert-butyl((S)-1-cyclopentyl-2-((2S,4R)-4-hydroxy-2-((4-(4-methylthiazol-5-yl)benzyl)carbamoyl)pyrrolidin-1-yl)-2-oxoethyl)carbamate(200 mg, 0.37 mmol) was suspended in DCM (1 mL) and treated with HCl indioxane (4 M, 1 mL, 4.0 mmol), followed by MeOH (0.5 mL). The reactionmixture was stirred at room temperature for 3 hours. The mixture wasevaporated to dryness to afford the title compound (160 mg, 0.33 mmol,89% yield). LCMS RT=0.61 min, ES+ve m/z 443.6 [M+H]⁺.

(2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride

A stirred mixture of(2S,4R)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (70 mg, 0.20 mmol) and(S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid(commercially available from for example Fluka) (50 mg, 0.22 mmol) inDMF (1 mL) was treated with DIPEA (0.14 mL, 0.79 mmol) and then withHATU (90 mg, 0.24 mmol), and stirred at ambient temperature for 30minutes. The reaction mixture was subjected directly to purification bymass-directed automated preparative HPLC (formic acid modifier) to givethe intermediate boc-protected product. The intermediate was thendissolved in a mixture of dichloromethane (0.5 mL) and methanol (0.1 mL)and treated with HCl in 1,4-dioxane (4M, 0.25 mL, 1.0 mmol). Afterstirring at ambient temperature for 1 hour, the reaction mixture wasevaporated to dryness and the residue triturated to a solid withdichloromethane and dried under vacuum to afford the title compound (76mg, 0.16 mmol, 82% yield). LCMS RT=0.58 min, ES+ve m/z 431.2 [M+H]⁺.

4-(Oxazol-5-yl)benzonitrile

A mixture of 4-formylbenzonitrile (commercially available from forexample Aldrich) (5.32 g, 41 mmol),1-((isocyanomethyl)sulfonyl)-4-methylbenzene (commercially availablefrom for example Aldrich) (8.83 g, 45 mmol) and potassium carbonate (7.3g, 53 mmol) in methanol (200 mL) was stirred at ambient temperature for80 minutes. The mixture was then evaporated to dryness; the residue wastreated with saturated aqueous sodium bicarbonate (100 mL) and extractedwith dichloromethane (3×100 mL). The combined organics were washed withbrine (75 mL), passed through a hydrophobic frit and then evaporated todryness to afford the title compound (7.19 g, 42 mmol, quantitative).LCMS RT=0.75 min, ES+ve m/z 171 [M+H]⁺.

(4-(Oxazol-5-yl)phenyl)methanamine

Under an atmosphere of nitrogen, an ice-cooled mixture of4-(oxazol-5-yl)benzonitrile (900 mg, 5.29 mmol) and cobalt(II) chloridehexahydrate (commercially available from for example Aldrich) (1.8 g,7.9 mmol) in methanol (50 mL) was treated portion-wise over 5 minuteswith sodium borohydride (1 g, 26 mmol). The mixture was stirred for 30minutes and then treated with water (50 mL) and concentrated aqueousammonia (20 mL). The mixture was extracted with chloroform (3×150 mL),the combined organics were evaporated to dryness and the product waspurified by chromatography on silica using a gradient elution from 0% to30% methanol in dichloromethane (+0.1% triethylamine) to afford thetitle compound (580 mg, 3.3 mmol, 63% yield). LCMS RT=0.35 min, ES+vem/z 175 [M+H]⁺.

(2S,4R)-tert-Butyl4-hydroxy-2-((4-(oxazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate

To a stirred solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(0.66 g, 2.9 mmol) in dry DMF (20 mL) were added(4-(oxazol-5-yl)phenyl)methanamine (0.5 g, 2.9 mmol) and DIPEA (1 mL,5.7 mmol). This solution was then ice-cooled and HATU (1.09 g, 2.9 mmol)was added. The reaction mixture was stirred with cooling for anadditional hour then treated with water (30 mL) and extracted with ethylacetate (3×100 mL). The combined organic phase was washed with saturatedaqueous sodium bicarbonate (60 mL), brine (60 mL), dried over magnesiumsulfate, filtered and evaporated to dryness. The product was purified bychromatography on silica using a gradient elution from 0% to 25%methanol in dichloromethane to afford the title compound (758 mg, 1.96mmol, 68% yield). LCMS RT=0.73 min, ES+ve m/z 388 [M+H]⁺.

(2S,4R)-4-Hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride

A solution of (2S,4R)-tert-butyl4-hydroxy-2-((4-(oxazol-5-yl)benzyl)carbamoyl)pyrrolidine-1-carboxylate(2.74 g, 7.1 mmol) in methanol (10 mL) and dichloromethane (15 mL) wastreated with hydrochloric acid (4 M in 1,4-dioxane) (8.8 mL, 35 mmol)and the mixture was stirred at ambient temperature for 24 hours. Themixture was evaporated to dryness. The residue was suspended inmethanol, filtered and dried under vacuum to afford the title compound(2.24 g, 6.9 mmol, 98% yield). LCMS RT=0.44 min, ES+ve m/z 288 [M+H]⁺.

(2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide,Hydrochloride

HATU (141 mg, 0.371 mmol) was added to a solution of(S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (86 mg,0.37 mmol),(2S,4R)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (100 mg, 0.31 mmol) and DIPEA (0.162 mL, 0.93 mmol) in DMF(4 mL). The reaction was stirred for 45 min at room temperature. Thereaction mixture was partitioned between EtOAc (20 mL) and water (20mL). The aqueous phase was back extracted with EtOAc and the organicphase washed with brine (10 mL). The combined organic extracts weredried using an hydrophobic frit and concentrated under reduced pressure.The residue was purified by chromatography on silica using a gradientelution from 0% to 10% methanol in dichloromethane to give the requiredintermediate (132 mg). HCl in dioxane (4M, 0.386 mL, 1.54 mmol) wasadded to a solution of the intermediate (132 mg) dissolved in DCM (2 mL)and MeOH (2 mL). The mixture was stirred at room temperature for 4 h andwas then concentrated under reduced pressure to afford the titlecompound (95 mg, 0.22 mmol, 70% yield) as a beige solid. LCMS RT=0.53min, ES+ve m/z 401.4 [M+H]⁺.

tert-Butyl2-(2-(2-(2-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate

A mixture of4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenol (200mg, 0.53 mmol), tert-butyl2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (265 mg, 0.63 mmol),K₂CO₃ (219 mg, 1.59 mmol) in DMF (3 mL) was heated at 85° C. for 16 h. Afurther aliquot of tert-butyl2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (265 mg, 0.63 mmol)was added and the reaction heated at 85° C. for further 24 h. Thereaction was cooled to room temperature and partitioned between EtOAc(25 mL) and water (25 mL). The organic extract was washed with brine (25mL), dried using a hydrophobic frit and concentrated under reducedpressure. The product was purified by chromatography on silica using agradient elution from 0% to 50% EtOAc in cyclohexane to afford the titlecompound (245 mg, 0.39 mmol, 74% yield). LCMS RT=1.48 min, ES+ve m/z625.4 [M+H]⁺.

2-(2-(2-(2-(4-((6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid

Under an atmosphere of nitrogen, an ice-cooled solution of tert-butyl2-(2-(2-(2-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(245 mg, 0.39 mmol) in dry dichloromethane (5 mL) was treated withpropane-1-thiol (commercially available from for example Aldrich) (0.178mL, 1.97 mmol) and then with aluminium chloride (commercially availablefrom for example Aldrich) (418 mg, 3.1 mmol). The reaction mixture wasstirred at room temperature for 16 h. A further aliquot ofpropane-1-thiol (0.178 mL, 1.96 mmol) and aluminium chloride (418 mg,3.1 mmol) were added and the reaction was stirred at room temperaturefor further 24 h. Aqueous HCl (2M, 20 mL) was added and the product wasextracted with EtOAc (2×25 mL). The organic extracts were combined,dried using a hydrophobic frit and concentrated under reduced pressure.The residue was purified by SPE on aminopropyl (NH₂): the column wasfirst washed with MeOH (3 column volumes) and the product released byelution with ammonia in methanol (2M, 3 column volumes). The ammoniafraction was concentrated under reduced pressure. The product wassubjected to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the title compound (33 mg, 0.061 mmol,16% yield) as a colourless glass. LCMS RT=0.90 min, ES+ve m/z 541.2[M+H]⁺.

Example 1(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (commercially available from for example Aldrich) (19 mg, 0.050mmol) was added to a mixture of2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (22 mg, 0.041 mmol),(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide, hydrochloride (23 mg, 0.049 mmol) and DIPEA(commercially available from for example Aldrich) (0.05 mL, 0.29 mmol)in DMF (0.8 mL). The reaction was left standing at room temperature for25 minutes. The reaction mixture was directly subjected to purificationby mass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (8 mg, 0.008 mmol, 21% yield) as a colourlessglass. LCMS RT=1.02 min, ES+ve m/z 953.5 [M+H]⁺.

Example 2(2S,4R)-4-Hydroxy-1-((S)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (20 mg, 0.053 mmol) was added to a mixture of2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (20 mg, 0.037 mmol)(2S,4R)-1-((S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (20 mg, 0.044 mmol) and DIPEA (0.05 mL, 0.29 mmol) in DMF(0.8 mL). The reaction was left standing at room temperature for 25minutes. The reaction mixture was directly subjected to purification bymass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (9 mg, 0.0096 mmol, 26% yield) as colourlessglass. LCMS RT=0.98 min, ES+ve m/z 939.5 [M+H]⁺.

Example 3(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (16 mg, 0.042 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (18 mg, 0.041 mmol),2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (15 mg, 0.028 mmol) and DIPEA (0.024 mL, 0.14 mmol) in DMF (0.8mL). The reaction was stirred for 45 min at room temperature. Thereaction mixture was directly subjected to purification by mass-directedautomated preparative HPLC (formic acid modifier) to afford the titlecompound (3 mg, 0.003 mmol, 12% yield) as a white solid. LCMS RT=0.98min, ES+ve m/z 923.2, 924.3 [M+H]⁺.

Example 4(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Under an atmosphere of nitrogen, an ice-cooled solution of tert-butyl2-(2-(2-(2-(4-((6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(290 mg, 0.46 mmol) in dry dichloromethane (15 mL) was treated withpropane-1-thiol (0.210 mL, 2.3 mmol) and aluminium chloride (495 mg, 3.7mmol). The reaction was stirred at room temperature for 6 h. Aqueous HCl(1M, 10 mL) were added and the product was extracted with EtOAc (50 mL).The organic extract was dried using a hydrophobic frit and concentratedunder reduced pressure. The residue was purified by SPE on aminopropyl(NH₂): the column was first washed with MeOH (3 column volumes) and theproduct released by elution with ammonia in methanol (2M, 4 columnvolumes). The ammonia fraction was concentrated under reduced pressureand the residue was partitioned between EtOAc (25 mL) and aqueous HCl(1M, 25 mL). The organic extract was dried using a hydrophobic frit andconcentrated under reduced pressure to give a yellow residue as (130mg).

70 mg of the obtained residue were dissolved in DMF (0.8 mL) and treatedwith(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (73 mg, 0.16 mmol) and DIPEA (0.15 mL, 0.859 mmol). HATU(60 mg, 0.16 mmol) was added to the stirred reaction mixture and thereaction was left standing at room temperature for 25 minutes. Thesolution was directly subjected to purification by mass-directedautomated preparative HPLC (formic acid modifier) to afford the titlecompound (20 mg, 0.021 mmol, 5% yield) as a yellow solid. LCMS RT=1.19min, ES+ve m/z 967.4 [M+H]⁺.

4-((6-Methoxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenol

Hydroquinone (commercially available from for example Aldrich) (133 mg,1.207 mmol) was dissolved in DMF (2 mL). NaH (60% w/w in mineral oil)(20 mg, 0.5 mmol) was added slowly followed by3-bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene 1-oxide (100 mg,0.24 mmol). The reaction mixture was stirred at room temperature for 3h. Water (10 mL) was added and the product was extracted with EtOAc (30mL). The organic extract was dried using a hydrophobic frit andconcentrated under reduced pressure. The residue was purified bychromatography on silica using a gradient elution from 0% to 100% ethylacetate in cyclohexane followed by a 0% to 20% methanol in ethyl acetategradient elution to afford a yellow solid (186 mg). This solid wasdissolved in THF (5 mL) and treated with LiAlH₄ in THF (1M, 1.3 mL, 1.3mmol).

The reaction was stirred at ambient temperature for 1 h. Aqueous NaOH(50%, 50 mL) was carefully added and the mixture was partitioned betweenEtOAc (50 mL) and water (50 mL). 2M HCl was added to reach pH 1 in theaqueous phase. The organic extract was dried using a hydrophobic fritand concentrated under reduced pressure. The product was purified bychromatography on silica using a gradient elution from 0% to 100% ethylacetate in cyclohexane to afford the title compound (90 mg, 0.26 mmol,80% pure, 86% yield) as a white solid. LCMS RT=1.29 min, ES+ve m/z 349.3[M+H]⁺.

tert-Butyl2-(2-(2-(2-(4-((6-methoxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate

A mixture of 4-((6-methoxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenol (90mg, 0.26 mmol), tert-butyl2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (216 mg, 0.517 mmol),K₂CO₃ (107 mg, 0.78 mmol) in DMF (2 mL) was heated at 85° C. for 16 h.The reaction was cooled to room temperature and partitioned betweenEtOAc (30 mL) and water (30 mL). The organic layer was dried using ahydrophobic frit and concentrated under reduced pressure. The productwas purified by chromatography on silica using a gradient elution from0% to 50% ethyl acetate in cyclohexane to afford the title compound (104mg, 0.18 mmol, 68% yield) as a yellow oil. LCMS RT=1.50 min, ES+ve m/z617.3 [M+Na]⁺.

Example 5(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Under an atmosphere of nitrogen, an ice-cooled solution of tert-butyl2-(2-(2-(2-(4-((6-methoxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(104 mg, 0.175 mmol) in dry dichloromethane (10 mL) was treated withpropane-1-thiol (0.048 mL, 0.525 mmol) followed by aluminium chloride(117 mg, 0.87 mmol). The reaction was stirred at room temperature for 3h. A further aliquot of propane-1-thiol (0.048 mL, 0.53 mmol) andaluminium chloride (117 mg, 0.874 mmol) was added and the suspension wassonicated for 10 minutes to help solubilise the reactants. The reactionwas then stirred at room temperature for 3 h. Aqueous HCl (1M, 10 mL)was added and the product was extracted with EtOAc (50 mL). The organicextract was dried using a hydrophobic frit and concentrated underreduced pressure. The residue was purified by SPE on aminopropyl (NH₂):the column was first washed with MeOH (3 column volumes) and the productreleased by elution with ammonia in methanol (2M, 4 column volumes). Theammonia fraction was concentrated under reduced pressure and the residuewas partitioned between EtOAc (25 mL) and aqueous HCl (1M, 25 mL). Theorganic extract was dried using a hydrophobic frit and concentratedunder reduced pressure to give a yellow residue (44 mg). This residuewas dissolved in DMF (0.8 mL) and treated with(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (59 mg, 0.13 mmol) and DIPEA (0.1 mL, 0.57 mmol). HATU (47mg, 0.12 mmol) was added to the solution which was stirred at roomtemperature for 10 min. The solution was then directly subjected topurification by mass-directed automated preparative HPLC (formic acidmodifier gradient) to afford the title compound (10 mg, 10.7 μmol, 6%yield) as a colourless glass. LCMS RT=1.20 min, ES+ve m/z 937.6 [M+H]⁺.

2-(4-Bromophenyl)-3-(4-(tert-butoxy)phenoxy)-6-methoxybenzo[b]thiophene1-oxide

4-(tert-Butoxy)phenol (2.56 g, 15.41 mmol) was dissolved in DMF (70 mL).NaH, in mineral oil (60% w/w, 0.840 g, 21 mmol) was added slowlyfollowed by 3-bromo-2-(4-bromophenyl)-6-methoxybenzo[b]thiophene 1-oxide(commercially available from for example Aldrich) (5.8 g, 14 mmol). Thereaction mixture was stirred at room temperature for 3 h. Water (100 mL)followed by aqueous HCl (2M, 20 mL) were added and the product wasextracted with EtOAc (200 mL). The organic extract was dried using MgSO₄and concentrated under reduced pressure to afford the title compound(5.8 g, 11.6 mmol, 83% yield). LCMS RT=1.41 min, ES+ve m/z 499.1/501.1[M+H]⁺.

4-((2-(4-Bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenol

TMSCl (commercially available from for example Aldrich) (3.84 mL, 30mmol) was added to a solution of2-(4-bromophenyl)-3-(4-(tert-butoxy)phenoxy)-6-methoxybenzo[b]thiophene1-oxide (1.5 g, 3 mmol) and triphenylphosphine (2.75 g, 10.5 mmol) inTHF (30 mL). The reaction mixture was stirred under reflux conditionsfor 3 h. The reaction was cooled to room temperature and water (100 mL)was added. The intermediate was extracted with EtOAc (200 mL). Theorganic extract was dried using a hydrophobic frit and concentratedunder reduced pressure. The intermediate was purified by chromatographyon silica using a gradient elution from 0% to 50% ethyl acetate incyclohexane to afford a yellow oil. The oil was dissolved in DCM (15 mL)and treated with HCl in dioxane (4M, 7.5 mL, 30 mmol). The reaction washeated for 3 h at 40° C. The solvent was removed under reduced pressureand the residue was partitioned between EtOAc (150 mL) and brine (150mL). The organic extract was dried using a hydrophobic frit andconcentrated under reduced pressure. The product was purified bychromatography on silica using a gradient elution from 0% to 35% ethylacetate in cyclohexane to afford the title compound (1 g, 2.3 mmol, 78%yield) as a white solid. LCMS RT=1.41 min, ES+ve m/z 427.1/429.1 [M+H]⁺.

tert-Butyl2-(2-(2-(2-(4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate

A mixture of4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenol (1 g,2.340 mmol), tert-butyl2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (2 g, 4.8 mmol), K₂CO₃(1 g, 7.2 mmol) in DMF (2 mL) was heated at 85° C. for 48 h. Thereaction was cooled to room temperature and partitioned between EtOAc(100 mL) and water (100 mL). The organic layer was dried using ahydrophobic frit and concentrated under reduced pressure. The productwas purified by chromatography on silica using a gradient elution from0% to 50% ethyl acetate in cyclohexane to afford the title compound(1.41 g, 2.1 mmol, 89% yield) as a yellow oil. LCMS RT=1.61 min, ES+vem/z 690.4/692.4 [M+NH₄]⁺.

Example 6(2S,4R)-1-((S)-14-(4-((2-(4-Bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Under an atmosphere of nitrogen, an ice-cooled solution of tert-butyl2-(2-(2-(2-(4-((2-(4-bromophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(225 mg, 0.33 mmol) in dry DCM (10 mL) was treated with propane-1-thiol(0.091 mL, 1.0 mmol) followed by aluminium chloride (223 mg, 1.7 mmol).The reaction was then stirred at room temperature for 5 h. Aqueous HCl(1M, 10 mL) was added and the product was extracted with EtOAc (50 mL).The organic extract was dried using a hydrophobic frit and concentratedunder reduced pressure. The residue was dissolved in DMF (3 mL) andtreated with DIPEA (0.3 mL, 1.718 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (234 mg, 0.5 mmol). HATU (191 mg, 0.5 mmol) was added andthe reaction was stirred at room temperature for 10 min. The solutionwas then subjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (72mg, 0.071 mmol, 21% yield) as a white solid. LCMS RT=1.30 min, ES+ve m/z1015.3/1017.3 [M+H]⁺.

3-(4-(tert-Butoxy)phenoxy)-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene1-oxide

4-(tert-Butoxy)phenol (393 mg, 2.37 mmol) was dissolved in DMF (15 mL).NaH in mineral oil (60% w/w, 172 mg, 4.3 mmol) was added slowly followedby 3-bromo-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene 1-oxide (760mg, 2.2 mmol). The reaction mixture was stirred at room temperature for2.5 h. Water (200 mL) was added and the product was extracted with EtOAc(200 mL). Aqueous HCl (2M) was added until the pH of aqueous phase was 1and the aqueous phase was extracted with EtOAc (200 mL). The combinedorganic extracts were washed with brine (300 mL), dried using ahydrophobic frit and concentrated under reduced pressure. The productwas purified by chromatography on silica using a gradient elution from0% to 50% ethyl acetate in dichloromethane to afford the title compound(815 mg, 1.86 mmol, 86% yield) as a yellow solid. LCMS RT=1.32 min,ES+ve m/z 439.3 [M+H]⁺.

3-(4-(tert-Butoxy)phenoxy)-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene

LiAlH₄ in THF (1M, 3.72 mL, 3.7 mmol) was added to a mixture of3-(4-(tert-butoxy)phenoxy)-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene1-oxide (815 mg, 1.86 mmol) in THF (15 mL). The reaction was stirred atambient temperature for 1.5 h. Aqueous NaOH (50%, 10 mL) was carefullyadded and the mixture was partitioned between EtOAc (100 mL) and water(100 mL). The aqueous phase was further extracted with EtOAc (3×100 mL).The organic extracts were combined, dried using a hydrophobic fit andconcentrated under reduced pressure. The product was purified bychromatography on silica using a gradient elution from 0% to 50%dichloromethane in cyclohexane to afford the title compound (560 mg,1.33 mmol, 71% yield) as a colourless gum. LCMS RT=1.61 min, ES+ve m/z423.0 [M+H]⁺.

4-((2-(4-Fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenol

3-(4-(tert-Butoxy)phenoxy)-2-(4-fluorophenyl)-6-methoxybenzo[b]thiophene(560 mg, 1.33 mmol) was dissolved in 1,4-dioxane (5 mL). HCl in dioxane(4M, 5 mL, 20 mmol) was added and the reaction mixture was stirredovernight at 60° C. The mixture was concentrated under reduced pressure.The residue was dissolved in acetonitrile and concentrated under reducedpressure to afford the title compound (450 mg, 1.2 mmol, 93% yield).LCMS RT=1.30 min, ES+ve m/z 367.2 [M+H]⁺.

tert-Butyl2-(2-(2-(2-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate

A mixture of4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenol (450mg, 1.228 mmol), tert-butyl2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (1.028 g, 2.46 mmol),K₂CO₃ (509 mg, 3.68 mmol) in DMF (6 mL) was heated at 80° C. for 72hours. The reaction was cooled to room temperature and partitionedbetween EtOAc (50 mL) and water (50 mL). The organic extract was washedwith brine (50 mL), dried using a hydrophobic frit and concentratedunder reduced pressure. The product was purified by chromatography onsilica using a gradient elution from 0% to 50% ethyl acetate incyclohexane to afford the title compound (600 mg, 0.98 mmol, 80% yield)as a colourless gum. LCMS RT=1.51 min, ES+ve m/z 635 [M+Na]⁺.

Example 7(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

Under an atmosphere of nitrogen, an ice-cooled solution of tert-butyl2-(2-(2-(2-(4-((2-(4-fluorophenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(240 mg, 0.39 mmol) in dry DCM (10 mL) was treated with propane-1-thiol(0.107 mL, 1.18 mmol) followed by aluminium chloride (261 mg, 1.96mmol). The reaction was then stirred at room temperature for 4 h. Afurther aliquot of aluminium chloride (130 mg, 0.98 mmol) was added andthe reaction was stirred at room temperature for a further hour. AqueousHCl (1M, 10 mL) was added and the product was extracted with EtOAc (50mL). The organic extract was dried using a hydrophobic frit andconcentrated under reduced pressure. The residue was purified by SPE onaminopropyl (NH₂): the column was first washed with MeOH (3 columnvolumes) and the product released by elution with ammonia in methanol(2M, 4 column volumes). The ammonia fraction was concentrated underreduced pressure and the residue was partitioned between EtOAc (25 mL)and aqueous HCl (1M, 25 mL). The organic extract was dried using ahydrophobic frit and concentrated under reduced pressure to give ayellow residue (126 mg). This residue was dissolved in DMF (1.6 mL) andtreated with DIPEA (0.342 mL, 1.96 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (163 mg, 0.35 mmol). HATU (132 mg, 0.347 mmol) was addedand the reaction was stirred at room temperature for 10 min. Thesolution was then directly subjected to purification by mass-directedautomated preparative HPLC (formic acid modifier) to afford the titlecompound (47 mg, 0.049 mmol, 13% yield) as an off-white solid. LCMSRT=1.21 min, ES+ve m/z 955.6 [M+H]⁺.

(4-Fluorophenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone

Under an atmosphere of nitrogen, an ice-cooled suspension of6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (commercially availablefrom for example Aldrich) (10 g, 37 mmol) in anhydrous dichloromethane(250 mL) was treated with aluminium chloride (5.9 g, 44 mmol) and thenwith 4-fluorobenzoyl chloride (commercially available from for exampleAldrich) (5.2 mL, 44 mmol). The mixture was stirred at 0° C. for 3 daysand then treated with 1M aqueous hydrochloric acid (200 mL) and stirredfor 20 minutes. The mixture was subsequently treated withdichloromethane (200 mL) and 1M aqueous hydrochloric acid (200 mL) andseparated. The aqueous phase was extracted with additionaldichloromethane (2×150 mL) and the organics were combined and evaporatedto dryness. The product was purified by chromatography on silica using agradient elution from 0% to 25% ethyl acetate in cyclohexane to affordthe title compound (12.7 g, 32 mmol, 87% yield). LCMS RT=1.40 min, ES+vem/z 393.3 [M+H]⁺.

(4-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)phenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone

Sodium hydride (60% w/w in mineral oil) (64 mg, 1.6 mmol) was added toan ice-cooled solution of 2,2′-(ethane-1,2-diylbis(oxy))diethanol(commercially available from for example Aldrich) (670 mg, 4.5 mmol) inDMF (3.5 mL). The reaction was stirred at 0° C. for 15 min and(4-fluorophenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone(350 mg, 0.89 mmol) was then added. The reaction mixture was warmed toroom temperature and stirred for a further 3 hours. The reaction mixturewas partitioned between DCM (40 mL) and water (40 mL). The mixture wasseparated and the aqueous phase was extracted with additional DCM (40mL). The combined organic extracts were evaporated to dryness and theproduct was purified by chromatography on silica (50 g cartridge) usinga gradient elution from 0% to 25% MeOH in DCM to afford the titlecompound (453 mg, 0.87 mmol, 93% yield). LCMS RT=1.17 min, ES+ve m/z523.3 [M+H]⁺.

(4-(2-(2-(2-(2-Hydroxyethoxy)ethoxy)ethoxy)ethoxy)phenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone

Under an atmosphere of nitrogen, an ice-cooled solution of(4-fluorophenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone(1.72 g, 4.4 mmol) and 2,2′-((oxybis(ethane-2,1-diyl))bis(oxy))diethanol(commercially available from for example Aldrich) (4.26 g, 22 mmol) indry DMF (20 mL) was treated with sodium hydride (60% w/w in mineral oil)(316 mg, 7.9 mmol) and the mixture was stirred with ice cooling for 15minutes then allowed to warm to ambient temperature. After 2 hours themixture was treated with water (50 mL) and dichloromethane (70 mL). Themixture was separated and the aqueous phase was extracted withdichloromethane (20 mL). The combined organics were evaporated todryness and the product was purified by chromatography on silica using agradient elution from 0% to 25% methanol in dichloromethane to affordthe title compound (2.34 g, 4.1 mmol, 94% yield). LCMS RT=1.18 min,ES+ve m/z 567 [M+F]⁺.

tert-Butyl2-(2-(2-(2-(4-(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)acetate

Sodium hydride, 60% w/w in mineral oil (69 mg, 1.7 mmol) was added to anice-cooled solution of(4-(2-(2-(2-hydroxyethoxy)ethoxy)ethoxy)phenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone(450 mg, 0.86 mmol) in DMF (3.3 mL). The reaction was stirred at 0° C.for 1 hour and tert-butyl 2-bromoacetate (commercially available fromfor example Aldrich) (0.25 mL, 1.7 mmol) was added. The reaction waswarmed to room temperature and stirred for a further 3 hours. Thereaction mixture was partitioned between ethyl acetate (30 mL) and water(30 mL). The organic layer was separated, washed with brine (30 mL),passed through a hydrophobic frit and evaporated to dryness. The productwas purified by chromatography on silica (50 g cartridge) using agradient elution from 0% to 100% ethyl acetate in cyclohexane to affordthe title compound (330 mg, 0.52 mmol, 60% yield). LCMS RT=1.40 min,ES-ve m/z 637.3 [M+H]⁺, 659.3 [M+Na]⁺.

2-(2-(2-(2-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid2-(2-(2-(2-(4-(6-Hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid2-(2-(2-(2-(4-(2-(4-Hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid

A cooled solution (0° C.) of tert-butyl2-(2-(2-(2-(4-(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)acetate(330 mg, 0.518 mmol) in dry DCM (7 mL) was treated with propane-1-thiol(commercially available from for example Aldrich) (0.188 mL, 2.1 mmol)and then with aluminium chloride (commercially available from forexample Aldrich) (290 mg, 2.2 mmol). The reaction was warmed to roomtemperature, and stirred for 3 hours. A further aliquot of aluminiumchloride (290 mg, 2.2 mmol) was added, and the reaction mixture wasstirred at room temperature overnight. The reaction mixture was treatedcautiously with 2M aqueous HCl (10 mL) and THF (20 mL). The organiclayer was separated and the aqueous layer was extracted with DCM (2×20mL). The combined organic layers were dried using a hydrophobic frit andconcentrated under reduced pressure. The crude product was dissolved inDMSO (4 mL) and subjected to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the three products:

2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (140 mg, 0.25 mmol, 49% yield). LCMS RT=0.84 min, ES+ve m/z 553.3[M+H]⁺.

2-(2-(2-(2-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (16 mg, 0.028 mmol, 5% yield). LCMS RT=0.99 min, ES+ve m/z 567.3[M+H]⁺.

2-(2-(2-(2-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (58 mg, 0.10 mmol, 20% yield). LCMS RT=1.04 min, ES+ve m/z 567.3[M+H]⁺.

14-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oicacid14-(4-(6-Hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oicacid14-(4-(2-(4-Hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oicacid

Under an atmosphere of nitrogen, an ice-cooled solution of tert-butyl14-(4-(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oate(480 mg, 0.71 mmol) in dry dichloromethane (10 mL) was treated withpropane-1-thiol (commercially available from for example Aldrich) (0.319mL, 3.5 mmol) and then with aluminium chloride (564 mg, 4.2 mmol). After3 hours the mixture was treated cautiously with 2M aqueous hydrochloricacid (10 mL) and then evaporated to dryness. The product was subjecteddirectly to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the three title compounds:

14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oic acid (220 mg, 0.37 mmol, 52%yield). LCMS RT=0.87 min, ES+ve m/z 597 [M+H]⁺.

14-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[13]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oic acid (24 mg, 0.039 mmol, 5.6%yield). LCMS RT=0.99 min, ES+ve m/z 610 [M+H]⁺.

14-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oicacid (53 mg, 0.087 mmol, 12% yield). LCMS RT=1.05 min, ES+ve m/z 610[M+H]⁺.

Example 8(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (27 mg, 0.071 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (38 mg, 0.081 mmol),2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (30 mg, 0.054 mmol) and DIPEA (0.095 mL, 0.54 mmol) in DMF (0.8mL). The reaction was stirred at room temperature for 30 min, and wasthen subjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (16mg, 0.017 mmol, 31% yield). LCMS RT=0.97 min, ES+ve m/z 966.4 [M+H]⁺.

Using a method analogous to that for(2S,4R)-1-((S)-2-(tert-butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamidethe following compounds were prepared:

Structure Example Name (R₁) Yield RT [M + H]+ Example 9(2S,4R)-4-Hydroxy-1- Me 67% 0.88 min 923.4 ((S)-14-(4-(6-hydroxy-2- (4-hydroxyphenyl)benzo[b] thiophene-3- carbonyl)phenoxy)-2-methyl-4-oxo-6,9,12- trioxa-3-azatetradecan- 1-oyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide Example 10(2S,4R)-1-((S)-2-Ethyl- Et 74% 0.91 min 937.5 14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3- carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3- azatetradecan-1-oyl)-4- hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide Example 11(2S,4R)-4-Hydroxy-1- ^(i)Pr 65% 0.93 min 951.5 ((S)-14-(4-(6-hydroxy-2-(4- hydroxyphenyl)benzo[b] thiophene-3- carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12- trioxa-3-azatetradecan- 1-oyl)-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide Example 12(2S,4R)-1-((S)-2- Cyclopropyl-14-(4-(6- hydroxy-2-(4-hydroxyphenyl)benzo[b]

70% 0.91 min 949.3 thiophene-3- carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3- azatetradecan-1-oyl)-4- hydroxy-N-(4-(4-methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide Example 13(2S,4R)-1-((S)-2- Cyclopentyl-14-(4-(6- hydroxy-2-(4-hydroxyphenyl)benzo[b] thiophene-3- carbonyl)phenoxy)-4-

72% 0.97 min 977.4 oxo-6,9,12-trioxa-3- azatetradecan-1-yl)-4-hydroxy-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamideExample 14 (2S,4R)-4-Hydroxy-1- ((S)-14-(4-(6-hydroxy-2- (4-hydroxyphenyl)benzo[b] thiophene-3- carbonyl)phenoxy)-2-

64% 0.97 min 965.5 isobutyl-4-oxo-6,9,12- trioxa-3-azatetradecan-1-oyl)-N-(4-(4- methylthiazol-5- yl)benzyl)pyrrolidine-2- carboxamide

Example 15(2S,4R)-4-Hydroxy-1-((S)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

A solution of14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oicacid (18 mg, 0.030 mmol) in DMF (0.7 mL) was treated with DIPEA (0.021mL, 0.12 mmol) and(2S,4R)-1-((S)-2-amino-3-methylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (22 mg, 0.048 mmol) and then with HATU (14 mg, 0.036 mmol)and the mixture was stirred for 30 minutes. The product was subjecteddirectly to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the title compound (25 mg, 0.025 mmol,83% yield). LCMS RT=0.94 min, ES+ve m/z 995.5 [M+H]⁺.

Example 16(2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

A solution of14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oicacid (18 mg, 0.030 mmol) in DMF (0.7 mL) was treated with DIPEA (0.021mL, 0.12 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (23 mg, 0.048 mmol) and then with HATU (14 mg, 0.036 mmol)and the mixture was stirred for 30 minutes. The product was subjecteddirectly to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the title compound (22 mg, 0.022 mmol,72% yield). LCMS RT=0.98 min, ES+ve m/z 1009.5 [M+H]⁺.

Example 17(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (27 mg, 0.071 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride) (38 mg, 0.081 mmol),2-(2-(2-(2-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (31 mg, 0.054 mmol) and DIPEA (0.095 mL, 0.54 mmol) in DMF (0.8mL). The reaction was stirred at room temperature for 30 min, and wasthen subjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (15mg, 0.015 mmol, 28% yield). LCMS RT=1.14 min, ES+ve m/z 979.5 [M+H]⁺.

Example 18(2S,4R)-1-((S)-2-(Tert-butyl)-14-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (11 mg, 0.028 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (15 mg, 0.032 mmol),2-(2-(2-(2-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy) ethoxy) acetic acid (13 mg, 0.022 mmol) and DIPEA (0.038 mL,0.22 mmol) in DMF (0.6 mL). The reaction was stirred at room temperaturefor 30 min, and was then subjected directly to purification bymass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (9 mg, 0.009 mmol, 43% yield). LCMS RT=1.09min, ES+ve m/z 979.5 [M+H]⁺.

Example 19(2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

A mixture of14-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oicacid (20 mg, 0.033 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (23 mg, 0.049 mmol) in DMF (0.7 mL) was treated with DIPEA(0.023 mL, 0.13 mmol) and then with HATU (15 mg, 0.039 mmol) and stirredat ambient temperature for 15 minutes. The product was subjecteddirectly to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the title compound (14 mg, 0.014 mmol,42% yield). LCMS RT=1.09 min, ES+ve m/z 1023.5 [M+H]⁺.

Example 20(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (21 mg, 0.056 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (29 mg, 0.065 mmol),2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)ethoxy)aceticacid (24 mg, 0.043 mmol) and DIPEA (0.076 mL, 0.43 mmol) in DMF (0.8mL). The reaction was stirred at room temperature for 30 min and wasthen subjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (26mg, 0.028 mmol, 64% yield). LCMS RT=0.94 min, ES+ve m/z 935.6 [M+H]⁺.

(4-Fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone

Under an atmosphere of nitrogen, an ice-cooled solution of(4-fluorophenyl)(6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophen-3-yl)methanone(5 g, 13 mmol) in dry DCM (50 mL) was treated cautiously with borontribromide in DCM (1M, 38 mL, 38 mmol), and the mixture was stirred withcooling for 2 hours. The mixture was treated cautiously with water (100mL) and then with DCM (50 mL) and MeOH (15 mL). The mixture waspartitioned and the aqueous phase was extracted with 10% MeOH in DCM(100 mL). The combined organic extracts were evaporated to dryness andthe product was purified by chromatography on silica using a gradientelution from 0% to 100% ethyl acetate in DCM to afford the titlecompound (3.95 g, 11 mmol, 85% yield). LCMS RT=0.98 min, ES+ve m/z 365.2[M+H]⁺.

(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone

A solution of(4-fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone(2.58 g, 7.1 mmol) in DMF (25 mL) was treated with sodium carbonate(3.00 g, 28.3 mmol) and then with benzyl bromide (2.53 mL, 21 mmol). Themixture was heated gradually to 75° C. and heated at that temperaturefor 6 hours, then at 60° C. overnight. The cooled mixture was treatedwith DCM (150 mL) and water (100 mL) and the organic phase wasseparated. The aqueous phase was extracted with additional DCM (50 mL)and the combined organic layers were evaporated to dryness. The productwas purified by chromatography on silica using a gradient elution from0% to 20% ethyl acetate in cyclohexane to afford the title compound(2.97 g, 5.5 mmol, 77% yield). LCMS RT=1.59 min, ES+ve m/z 545.2 [M+H]⁺.

(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(2-(2-hydroxyethoxy)ethoxy)phenyl)methanone

Sodium hydride, 60% w/w in mineral oil (40 mg, 0.99 mmol) was added toan ice-cooled solution of 2,2′-oxydiethanol (commercially available fromfor example Aldrich) (292 mg, 2.8 mmol) in dry DMF (3 mL), and themixture was stirred for 30 min.(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone(300 mg, 0.55 mmol) was added, and the reaction mixture was warmed toambient temperature, and stirred for a further 18 hours. The mixture wastreated with water (50 mL) and DCM (50 mL), and the organic phase wasseparated. The aqueous phase was extracted with additional DCM (50 mL).The combined organic extracts were evaporated to dryness and the productwas purified by chromatography on silica (50 g cartridge) using agradient elution from 0% to 25% MeOH in DCM to afford the title compound(260 mg, 0.41 mmol, 75% yield). LCMS RT=1.45 min, ES+ve m/z 631.4[M+H]⁺.

tert-Butyl2-(2-(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)acetate

Sodium hydride, 60% w/w in mineral oil (25 mg, 0.634 mmol) was added toa cooled solution (0° C.) of(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(2-(2-hydroxyethoxy)ethoxy)phenyl)methanone(200 mg, 0.32 mmol) in DMF (1.2 mL). The reaction was stirred at 0° C.for 1 hour and tert-butyl 2-bromoacetate (commercially available fromfor example Aldrich) (0.094 mL, 0.63 mmol) was added. The reaction waswarmed to room temperature and stirred for 3 hours. The reaction mixturewas partitioned between ethyl acetate (30 mL) and water (30 mL). Theorganic layer was separated, washed with brine (30 mL), dried using ahydrophobic frit and concentrated under reduced pressure. The productwas purified by chromatography on silica (50 g cartridge) using agradient elution from 0% to 100% ethyl acetate in cyclohexane to affordthe title compound (200 mg, 0.23 mmol, 74% yield). LCMS RT=1.59 min,ES+ve m/z 745.5 [M+H]⁺.

2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)aceticacid

A mixture of tert-butyl2-(2-(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)acetate(200 mg, 0.27 mmol), 10% w/w palladium on carbon (29 mg, 0.027 mmol),ammonium formate (339 mg, 5.4 mmol) and water (0.19 mL, 11 mmol) in DMF(2.6 mL) was heated at 50° C. for 2 hours. The reaction mixture wasfiltered through celite, washed with ethyl acetate, and the filtrate wasconcentrated under reduced pressure. The crude material was dissolved inTFA (1.5 mL) and was stirred at room temperature for 10 min. Thereaction mixture was concentrated, and a 1:1 mixture of 25% aqueousHCl/THF (3 mL) was added. The crude mixture was then subjected directlyto purification by mass-directed automated preparative HPLC (formic acidmodifier) to afford the title compound (51 mg, 0.10 mmol, 37% yield).LCMS RT=0.84 min, ES+ve m/z 509.3 [M+H]⁺.

Example 21(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (25 mg, 0.066 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (31 mg, 0.066 mmol),2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)aceticacid (26 mg, 0.051 mmol) and DIPEA (0.089 mL, 0.51 mmol) in DMF (0.6mL). The reaction was stirred at room temperature for 30 min, and wasthen subjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (33mg, 0.035 mmol, 69% yield) LCMS RT=0.96 min, ES+ve m/z 921.4 [M+H]⁺.

tert-Butyl(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)(methyl)carbamate

Sodium hydride, 60% w/w in mineral oil (54 mg, 1.35 mmol) was added to acooled solution (0° C.) of tert-butyl (2-hydroxyethyl)(methyl)carbamate(commercially available from for example Chem-impex) (225 mg, 1.29 mmol)in DMF (3 mL) and the mixture was stirred at 0° C. for 15 min.(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone(350 mg, 0.64 mmol) was added and the reaction was slowly warmed to roomtemperature and stirred for 18 hours. The mixture was treated cautiouslywith water (40 mL) and ethyl acetate (40 mL). The organic phase wasseparated and the aqueous phase was extracted with additional ethylacetate (40 mL). The combined organic extracts were washed with water(40 mL), brine (40 mL) and evaporated under reduced pressure to affordthe title compound (445 mg, 0.64 mmol, 99% yield). LCMS RT=1.63 min,ES+ve m/z 700.5 [M+H]⁺, 722.3 [M+Na]⁺.

(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(2-(methylamino)ethoxy)phenyl)methanone,hydrochloride

HCl in dioxane (4 M, 1.6 mL, 6.4 mmol) was added to a solution oftert-butyl(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)(methyl)carbamate(445 mg, 0.64 mmol) in DCM (2 mL) and the mixture was stirred at roomtemperature for 1 hour. The solvent was removed under reduced to affordthe title compound (400 mg, 0.63 mmol, 98% yield). LCMS RT=1.16 min,ES+ve m/z 600.3 [M+H]⁺.

tert-Butyl2-(2-(2-((2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)(methyl)amino)ethoxy)ethoxy)acetate

A vial was charged with(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(2-(methylamino)ethoxy)phenyl)methanone,hydrochloride (140 mg, 0.22 mmol), tert-butyl2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (99 mg, 0.26 mmol), DIPEA (0.15mL, 0.88 mmol) and DMF (1.5 mL). The vial was sealed and the reactionwas heated at 80° C. for 18 hours. Additional tert-butyl2-(2-(2-(tosyloxy)ethoxy)ethoxy)acetate (99 mg, 0.26 mmol) was added andthe reaction was stirred at 80° C. for a further 24 hours. The reactionwas cooled to room temperature and the mixture was then subjecteddirectly to purification by mass-directed automated preparative HPLC(ammonium bicarbonate modifier) to afford the title compound (85 mg,0.11 mmol, 48% yield). LCMS RT=1.31 min, ES+ve m/z 802.4 [M+H]⁺.

2-(2-(2-((2-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)(methyl)amino)ethoxy)ethoxy)aceticacid, hydrochloride

A mixture of tert-butyl2-(2-(2-((2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)(methyl)amino)ethoxy)ethoxy)acetate(80 mg, 0.1 mmol), 10% w/w palladium on carbon (11 mg, 0.01 mmol),ammonium formate (126 mg, 2 mmol) and water (0.072 mL, 4 mmol) in DMF (1mL) was heated at 50° C. for 1 hour. The reaction mixture was filteredthrough celite, washed with ethyl acetate, and the filtrate wasconcentrated under reduced pressure. The crude material was thendissolved in TFA (1 mL) and was stirred at room temperature for 10 min.The reaction mixture was concentrated, and a 1:1 mixture of 25% aqueousHCl/THF (3 mL) was added. The crude mixture was then subjected directlyto purification by mass-directed automated preparative HPLC (formic acidmodifier) to afford the title compound (37 mg, 0.061 mmol, 62% yield).LCMS RT=0.68 min, ES+ve m/z 566.3 [M+H]⁺.

Example 22(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-12-methyl-4-oxo-6,9-dioxa-3,12-diazatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (25 mg, 0.066 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (35 mg, 0.075 mmol),2-(2-(2-((2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)(methyl)amino)ethoxy)ethoxy)acetic acid, hydrochloride (30 mg, 0.050 mmol) and DIPEA(0.087 mL, 0.5 mmol) in DMF (0.8 mL). The reaction was stirred at roomtemperature for 30 min, and was then subjected directly to purificationby mass-directed automated preparative HPLC (formic acid modifier). Theproduct contained a small amount of impurity, and was thereforedissolved in a 1:1 mixture of MeOH and DMSO (1 mL), and subjected topurification by mass-directed automated preparative HPLC using anammonium bicarbonate modifier to afford the title compound (24 mg, 0.025mmol, 49% yield). LCMS RT=0.80 min, ES+ve m/z 978.5 [M+H]⁺.

tert-Butyl15-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-13-methyl-3,6,9-trioxa-13-azapentadecan-1-oate

A vial was charged with(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(2-(methylamino)ethoxy)phenyl)methanone,hydrochloride (150 mg, 0.24 mmol), tert-butyl2-(2-(2-(3-(tosyloxy)propoxy)ethoxy)ethoxy)acetate (143 mg, 0.33 mmol),DIPEA (0.165 mL, 0.94 mmol) and DMF (1.4 mL). The vial was sealed andthe reaction was heated at 80° C. for 18 hours. The reaction was cooledto room temperature and the mixture was then subjected directly topurification by mass-directed automated preparative HPLC (ammoniumbicarbonate modifier) to afford the title compound (90 mg, 0.11 mmol,44% yield). LCMS RT=1.32 min, ES+ve m/z 860.5 [M+H]⁺.

15-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-13-methyl-3,6,9-trioxa-13-azapentadecan-1-oicacid, hydrochloride

A mixture of tert-butyl15-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-13-methyl-3,6,9-trioxa-13-azapentadecan-1-oate(90 mg, 0.11 mmol), 10% w/w palladium on carbon (11 mg, 0.01 mmol),ammonium formate (132 mg, 2.1 mmol) and water (0.075 mL, 4.2 mmol) inDMF (1 mL) was heated at 50° C. for 1 hour. The reaction mixture wasfiltered through celite, washed with ethyl acetate, and the filtrate wasconcentrated under reduced pressure. The crude material was dissolved inTFA (1 mL) and was stirred at room temperature for 10 min. The reactionmixture was concentrated, and a 1:1 mixture of 25% aqueous HCl/THF (2mL) was added. The crude mixture was then subjected directly topurification by mass-directed automated preparative HPLC (formic acidmodifier) to afford the title compound (60 mg, 0.091 mmol, 87% yield).LCMS RT=0.69 min, ES+ve m/z 624.4 [M+H]⁺.

Example 23(2S,4R)-1-((S)-2-(tert-Butyl)-18-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-16-methyl-4-oxo-6,9,12-trioxa-3,16-diazaoctadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

HATU (37 mg, 0.098 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (53 mg, 0.11 mmol),15-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-13-methyl-3,6,9-trioxa-13-azapentadecan-1-oicacid, hydrochloride (50 mg, 0.076 mmol) and DIPEA (0.132 mL, 0.76 mmol)in DMF (0.8 mL). The reaction was stirred at room temperature for 30min, and was then subjected directly to purification by mass-directedautomated preparative HPLC (formic acid modifier). The product containeda small amount of impurity, and was therefore dissolved in a 1:1 mixtureof MeOH and DMSO (1 mL), and subjected to purification by mass-directedautomated preparative HPLC using an ammonium bicarbonatemodifier toafford the title compound (38 mg, 0.037 mmol, 48% yield). LCMS RT=0.82min, ES+ve m/z 1036.5 [M+H]⁺.

(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)phenyl)methanone

A solution of(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone(320 mg, 0.59 mmol) in NMP (3 mL) was sealed and heated in a Biotage“Initiator” microwave at 160° C. for 1 hr. The cooled product wassubjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound(181 mg, 0.26 mmol, 44% yield). LCMS RT=1.19 min, ES+ve m/z 699 [M+H]⁺.

tert-Butyl2-(2-(2-(4-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)acetate

Under an atmosphere of nitrogen, a solution of(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)phenyl)methanone(120 mg, 0.17 mmol) in DMF (5 mL) was treated with tert-butylbromoacetate (0.1 mL, 0.69 mmol) and then with sodium hydride (60% inmineral oil) (41 mg, 1.03 mmol) and stirred at ambient temperatureovernight. The mixture was treated with 5% aqueous ammonium chloride (30mL) and extracted with dichloromethane (30 mL). The organic fraction wasevaporated to dryness and the product was subjected to purification bymass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (80 mg, 0.098 mmol, 57% yield). LCMS RT=1.28min, ES+ve m/z 813 [M+H]⁺.

2-(2-(2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)aceticacid

A solution of tert-butyl2-(2-(2-(4-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)acetate(80 mg, 0.098 mmol) in a mixture of DMF (2 mL) and water (0.2 mL) wastreated with ammonium formate (62 mg, 0.98 mmol) and palladium on carbon(10% degussa type) (18 mg, 0.017 mmol) and stirred at 50° C. for 1 hour.The cooled mixture was filtered and evaporated to dryness. The residuewas treated with TFA (5 mL), stirred for 1 hour and then evaporated todryness. The product was subjected directly to purification bymass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (34 mg, 0.059 mmol, 60% yield). LCMS RT=0.67min, ES+ve m/z 577 [M+H]⁺.

Example 24(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

A mixture of2-(2-(2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)aceticacid (25 mg, 0.036 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (26 mg, 0.055 mmol) in DMF (0.7 mL) was treated with DIPEA(0.045 mL, 0.26 mmol) and then with HATU (17 mg, 0.044 mmol) and stirredat ambient temperature for 15 minutes. The product was subjecteddirectly to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the title compound (12 mg, 0.012 mmol,33% yield). LCMS RT=0.84 min, ES+ve m/z 989 [M+H]⁺.

(6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)phenyl)methanone

Under an atmosphere of nitrogen, a solution of(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-fluorophenyl)methanone(300 mg, 0.55 mmol) in DMF (1 mL) was treated with2,2′-(piperazine-1,4-diyl)diethanol (384 mg, 2.2 mmol) and then withsodium hydride (60% in mineral oil) (44 mg, 1.1 mmol) and the mixturewas heated at 50° C. overnight. The cooled mixture was treated with 4MHCl in 1,4-dioxane (0.1 mL) and then the product was subjected directlyto purification by mass-directed automated preparative HPLC (formic acidmodifier) to afford the title compound (177 mg, 0.25 mmol, 46% yield).LCMS RT=1.21 min, ES+ve m/z 699 [M+H]⁺.

tert-Butyl2-(2-(4-(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetate

Under an atmosphere of nitrogen, a solution of(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)(4-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)phenyl)methanone(120 mg, 0.17 mmol) in DMF (3 mL) was treated with tert-butylbromoacetate (0.051 mL, 0.34 mmol) and then with sodium hydride (60% inmineral oil) (28 mg, 0.69 mmol) and stirred at ambient temperatureovernight. The mixture was treated with 5% aqueous ammonium chloride (20mL) and extracted with dichloromethane (30 mL). The organic phase wasevaporated to dryness and the product was subjected to purification bymass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (88 mg, 0.11 mmol, 63% yield). LCMS RT=1.30min, ES+ve m/z 813 [M+H]⁺.

2-(2-(4-(2-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)aceticacid

A solution of tert-butyl2-(2-(4-(2-(4-(6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetate(80 mg, 0.098 mmol) in a mixture of DMF (2 mL) and water (150 μl) wastreated with ammonium formate (62 mg, 0.98 mmol) and palladium on carbon(10% degussa type) (18 mg, 0.017 mmol) and stirred at 50° C. for 1 hour.The cooled mixture was filtered and the filtrate evaporated to dryness.The residue was treated with TFA (5 mL), stirred for 1 hour and thenevaporated to dryness. The product was subjected to purification bymass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (22 mg, 0.038 mmol, 39% yield). LCMS RT=0.67min, ES+ve m/z 577 [M+H]⁺.

Example 25(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(4-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

A mixture of2-(2-(4-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)aceticacid (25 mg, 0.036 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (26 mg, 0.055 mmol) in DMF (0.7 mL) was treated with DIPEA(0.045 mL, 0.26 mmol) and then with HATU (17 mg, 0.044 mmol) and stirredat ambient temperature for 15 minutes. The product was subjecteddirectly to purification by mass-directed automated preparative HPLC(formic acid modifier) to the title compound (18 mg, 0.018 mmol, 50%yield). LCMS RT=0.91 min, ES+ve m/z 989 [M+H]⁺.

tert-Butyl4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazine-1-carboxylate

A solution of(4-fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone(300 mg, 0.82 mmol) in N-methyl-2-pyrrolidone (4 mL) was sealed andheated in a Biotage “Initiator” microwave at 140° C. for 90 min. Theproduct was subjected directly to purification by mass-directedautomated preparative HPLC (formic acid modifier) to afford the titlecompound (221 mg, 0.36 mmol, 44% yield). LCMS RT=0.81 min, ES+ve m/z 614[M+H]⁺.

(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)methanone,hydrochloride

tert-Butyl4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazine-1-carboxylate(221 mg, 0.36 mmol) was dissolved in trifluoroacetic acid (4 mL). After30 minutes the solution was evaporated to dryness, the residue was takenup in THF (10 mL), treated with 4M HCl in 1,4-dioxane (2 mL) andevaporated to dryness to afford the title compound (174 mg, 0.32 mmol,89% yield). LCMS RT=0.64 min, ES+ve m/z 514 [M+H]⁺.

tert-Butyl2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)acetate

A solution of(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)(4-(4-(piperazin-1-yl)piperidin-1-yl)phenyl)methanone(300 mg, 0.58 mmol) in DMF (1 mL) was treated with sodium bicarbonate(245 mg, 2.9 mmol) and tert-butyl bromoacetate (0.129 mL, 0.88 mmol) andthe mixture was stirred at ambient temperature for 3 days. The productwas subjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound(160 mg, 0.26 mmol, 44% yield). LCMS RT=0.79 min, ES+ve m/z 628 [M+H]⁺.

2-(4-(1-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)aceticacid, 3 hydrochloride

A solution of tert-butyl2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)acetate(160 mg, 0.26 mmol) in THF (10 mL) and treated with 25% aqueous HCl (5mL) and after 1 hour blown to dryness in a stream of nitrogen to affordthe title compound (164 mg, 0.24 mmol, 92% yield). LCMS RT=0.65 min,ES+ve m/z 572 [M+H]⁺.

Example 26(2S,4R)-4-hydroxy-1-((S)-2-(2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

A mixture of2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperidin-4-yl)piperazin-1-yl)aceticacid, 3 hydrochloride (37 mg, 0.054 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (38 mg, 0.081 mmol) in DMF (0.7 mL) was treated with DIPEA(0.066 mL, 0.38 mmol) and then with HATU (25 mg, 0.065 mmol) and stirredat ambient temperature for 15 minutes. The product was subjecteddirectly to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the title compound (22 mg, 0.022 mmol,41% yield). LCMS RT=0.83 min, ES+ve m/z 984 [M+H]⁺.

tert-Butyl9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate

A mixture of(4-fluorophenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone(200 mg, 0.55 mmol) and tert-butyl3,9-diazaspiro[5.5]undecane-3-carboxylate (commercially available fromfor example Matrix Scientific) (279 mg, 1.1 mmol) was heated in aBiotage microwave at 130° C. for 4 hours. The reaction mixture wascooled to room temperature, diluted with DMF (3 mL), and was thensubjected directly to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound(215 mg, 0.36 mmol, 65% yield). LCMS RT=1.22 min, ES+ve m/z 599.5[M+H]⁺.

(4-(3,9-Diazaspiro[5.5]undecan-3-yl)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone,2 hydrochloride

HCl in dioxane (4 M, 1.5 mL, 6.0 mmol) was added to a solution oftert-butyl9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecane-3-carboxylate(215 mg, 0.36 mmol) in a mixture of DCM (1 mL) and MeOH (0.5 mL), andthe mixture was stirred at room temperature for 18 hours. The solventwas removed under reduced to afford the title compound (190 mg, 0.33mmol, 93% yield). LCMS RT=0.72 min, ES+ve m/z 499.1 [M+H]⁺.

tert-Butyl2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetate,formic acid salt

A vial was charged with(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone,2 hydrochloride (43 mg, 0.075 mmol), tert-butyl 2-bromoacetate(commercially available from for example Aldrich) (0.013 mL, 0.09 mmol)and sodium bicarbonate (32 mg, 0.38 mmol) in DMF (0.6 mL). The vial wassealed and the reaction was heated at 50° C. for 2 hours. The reactionwas cooled to room temperature, filtered and was subjected directly topurification by mass-directed automated preparative HPLC (formic acidmodifier) to afford the title compound (37 mg, 0.056 mmol, 75% yield).LCMS RT=0.84 min, ES+ve m/z 613.4 [M+H]⁺.

2-(9-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)aceticacid, 2 hydrochloride

tert-Butyl2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetate,formic acid salt (37 mg, 0.056 mmol) was treated cautiously with TFA(0.5 mL) and the mixture was stirred at room temperature for 30 min. Thereaction mixture was concentrated, treated with HCl in dioxane (4M, 2mL), and was stirred at room temperature for 30 min. The solvent wasremoved under reduced to afford the title compound (35 mg, 0.056 mmol,100% yield). LCMS RT=0.74 min, ES+ve m/z 557.1 [M+H]⁺.

Example 27(2S,4R)-4-Hydroxy-1-((S)-2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,formic acid salt

HATU (24 mg, 0.062 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (33 mg, 0.071 mmol),2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)aceticacid, 2 hydrochloride (30 mg, 0.048 mmol) and DIPEA (0.083 mL, 0.476mmol) in DMF (0.6 mL). The reaction was stirred at room temperature for30 min, and was then subjected directly to purification by mass-directedautomated preparative HPLC (formic acid modifier) to afford the titlecompound (20 mg, 0.02 mmol, 41% yield). LCMS RT=0.85 min, ES+ve m/z969.4 [M+H]⁺.

tert-Butyl2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)acetate,formic acid salt

A vial was charged with(4-(3,9-diazaspiro[5.5]undecan-3-yl)phenyl)(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)methanone,2 hydrochloride (43 mg, 0.075 mmol), tert-butyl2-(2-(tosyloxy)ethoxy)acetate (0.028 mL, 0.11 mmol) and sodiumbicarbonate (32 mg, 0.38 mmol) in DMF (0.6 mL). The vial was sealed andthe reaction was heated at 60° C. for 20 hours. The reaction was cooledto room temperature, filtered and was subjected directly to purificationby mass-directed automated preparative HPLC (formic acid modifier) toafford the title compound (34 mg, 0.048 mmol, 64% yield). LCMS RT=0.88min, ES+ve m/z 657.4 [M+H]⁺.

2-(2-(9-(4-(6-Hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)aceticacid, 2 hydrochloride

tert-Butyl2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)acetate,formic acid salt (34 mg, 0.048 mmol) was treated cautiously with TFA(0.5 mL) and the mixture was stirred at room temperature for 10 min. Thereaction mixture was concentrated, treated with HCl in dioxane (4M, 2mL), and was stirred at room temperature for 30 min. The solvent wasremoved under reduced to afford the title compound (32 mg, 0.048 mmol,100% yield). LCMS RT=0.77 min, ES+ve m/z 601.3 [M+H]⁺.

Example 28(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,2 formic acid salt

HATU (13 mg, 0.035 mmol) was added to a mixture of(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (16 mg, 0.035 mmol),2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)aceticacid, 2 hydrochloride (18 mg, 0.027 mmol) and DIPEA (0.047 mL, 0.27mmol) in DMF (0.6 mL). The reaction was stirred at room temperature for30 min, and was then subjected directly to purification by mass-directedautomated preparative HPLC (formic acid modifier) to afford the titlecompound (3.3 mg, 3.0 μmol, 11% yield), LCMS RT=0.84 min, ES+ve m/z1013.5 [M+H]⁺, 507.7 [M/2+H]⁺.

Example 29(2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

A mixture of14-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-3,6,9,12-tetraoxatetradecan-1-oicacid (20 mg, 0.033 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide,hydrochloride (23 mg, 0.049 mmol) in DMF (0.7 mL) was treated with DIPEA(0.023 mL, 0.13 mmol) and then with HATU (15 mg, 0.039 mmol) and stirredat ambient temperature for 15 minutes. The product was subjecteddirectly to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the title compound (12 mg, 0.014 mmol,36% yield). LCMS RT=1.14 min, ES+ve m/z 1023.5 [M+H]⁺.

3-Bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene can be preparedaccording to the process described by Palkowitz, Alan David, U.S. Pat.No. 5,492,922A.

3-Bromo-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol

BBr₃ (commercially available from for example Aldrich) (2.274 mL, 24.05mmol) was added to a suspension of3-bromo-6-methoxy-2-(4-methoxyphenyl)benzo[b]thiophene (2.8 g, 8.02mmol) in dichloromethane (100 mL) stirring at 0° C. under an atmosphereof nitrogen. The reaction was stirred for 2 hours at that temperature.Water (100 mL) was carefully added and the product was extracted withethyl acetate (200 mL). The aqueous layer was washed with ethyl acetate(200 mL) and the organic fractions were then combined, washed with brine(2×200 mL), dried with MgSO₄ and concentrated under reduced pressure toafford the title compound (2.34 g, 7.29 mmol, 91% yield) as a beigesolid. LCMS RT=0.97 min, ES+ve m/z 320.5/322.1 [M+H]⁺.

6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-bromobenzo[b]thiophene 1-oxide

3-Bromo-2-(4-hydroxyphenyl)benzo[b]thiophen-6-ol (2.12 g, 6.60 mmol) wasdissolved in N,N-dimethylformamide (50 mL) and stirred at 0° C. NaH, 60%w/w in mineral oil (0.792 g, 19.80 mmol) was added and the reaction wasstirred at 0° C. for 10 minutes. (Bromomethyl)benzene (commerciallyavailable from for example Aldrich) (2.4 mL, 20.18 mmol) was added andthe reaction stirred at room temperature overnight. A saturated solutionof NH₄Cl (10 mL) was added cautiously followed by water (100 ml). Theproduct was extracted with ethyl acetate (200 mL). The organic phase waswashed with brine (100 mL) and concentrated. The intermediate waspurified by chromatography on silica using a gradient elution from 0% to50% ethyl acetate in cyclohexane. The appropriate fraction wasevaporated to give the required crude intermediate (2 g). To a solutionof the obtained compound (2 g) in dichloromethane (20 mL) was addedtrifluoroacetic acid (20 mL). The reaction was cool to 0° C. and after 5minutes of stirring, H₂O₂, 30% w/w in water (0.489 mL, 4.79 mmol) wasadded. The resulting mixture was stirred at 0° C. for 30 minutes and atroom temperature for 1 h. Solid sodium bisulfite (0.265 g) was addedcautiously to the dark solution followed by 3 mL of water. The mixturewas stirred vigorously for 15 minutes and then concentrated in vacuo.The residue was partitioned between dichloromethane (80 mL) andsaturated NaHCO₃ solution (80 mL). The layers were separated, and theorganic phase was extracted with saturated NaHCO₃ solution. The organicphase was then dried using a hydrophobic frit and concentrated in vacuo.The obtained solid was triturated with Et₂O/EtOAc and the brown solidwas filtrated to afford the title compound (780 mg, 1.507 mmol, 23%yield). LCMS RT=1.47 min, ES+ve m/z 517.2/519.1 [M+H]⁺.

6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-(4-(tert-butoxy)phenoxy)benzo[b]thiophene

4-(tert-Butoxy)phenol (302 mg, 1.815 mmol) was dissolved inN,N-dimethylformamide (15 mL). NaH, 60% w/w in mineral oil (132 mg, 3.30mmol) was added slowly followed by6-(benzyloxy)-2-(4-(benzyloxy)phenyl)-3-bromobenzo[b]thiophene 1-oxide(854 mg, 1.650 mmol). The reaction mixture was stirred at roomtemperature for 1.5 h. Water (300 mL) was added and the product wasextracted with EtOAc (300 mL). 2M aqueous HCl was added until the pH ofaqueous phase was 1 and the aqueous phase was extracted with EtOAc (400mL). The combined organic extracts were washed with brine (300 mL),dried using a hydrophobic frit and concentrated under reduced pressureto give the crude intermediate (1.08 g) as a brown solid. LiAlH₄ in THF(1M, 4.48 mL, 4.48 mmol) was added to a mixture of the obtainedintermediate (1.08 g) in tetrahydrofuran (20 mL). The reaction wasstirred at ambient temperature for 1.5 h. Aqueous NaOH (50%, 15 mL) wascarefully added and the mixture was partitioned between EtOAc (100 mL)and water (100 mL). The aqueous phase was further extracted with EtOAc(3×100 mL). The organic extracts were combined, dried using ahydrophobic frit and concentrated under reduced pressure. The productwas purified by chromatography on silica using a gradient elution from0% to 50% dichloromethane in cyclohexane followed by a 100%dichloromethane wash of the column to afford the title compound (440 mg,0.75 mmol, 45% yield). LCMS RT=1.71 min, ES+ve m/z 587.3 [M+H]⁺.

4-((6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)oxy)phenol

6-(Benzyloxy)-2-(4-(benzyloxy)phenyl)-3-(4-(tert-butoxy)phenoxy)benzo[13]thiophene (440 mg, 0.750 mmol) was dissolved in1,4-dioxane (20 mL). HCl in dioxane (4M, 1.875 mL, 7.50 mmol) was addedand the reaction was stirred at 40° C. for 60 h. A further aliquot ofHCl in dioxane (4M, 1.875 mL, 7.50 mmol) was added and the reaction wasstirred at 60° C. for 4 h. The reaction mixture was evaporated underreduced pressure to afford the title compound (405 mg, 0.763 mmol, >100%yield). LCMS RT=1.53 min, ES+ve m/z 531.2 [M+H]⁺

tert-Butyl2-(2-(2-(2-(4-((6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate

A mixture of4-((6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)oxy)phenol(4.03 g, 7.59 mmol), tert-butyl2-(2-(2-(2-(tosyloxy)ethoxy)ethoxy)ethoxy)acetate (5.40 g, 12.91 mmol),K₂CO₃ (316 mg, 2.290 mmol) in N,N-dimethylformamide (60 mL) was heatedat 85° C. for 48 h. The reaction was cooled to room temperature andpartitioned between EtOAc (600 mL) and water (600 mL). The organicextract was dried with MgSO₄, filtered using an hydrophobic frit andconcentrated under reduced pressure. The product was purified bychromatography on silica using a gradient elution from 0 to 50% TBME incyclohexane to afford the title compound (2 g, 2.57 mmol, 34% yield) asa brown oil. LCMS RT=1.64 min, ES+ve m/z 799.6 [M+Na]⁺

tert-Butyl2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate

A mixture of tert-butyl2-(2-(2-(2-(4-((6-(benzyloxy)-2-(4-(benzyloxy)phenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(2 g, 2.57 mmol) and palladium on carbon (10% w/w, 1.096 g, 1.030 mmol)in ethyl acetate (100 mL) and HCl in EtOH (1%, 15.67 mL, 5.16 mmol) wasstirred at room temperature overnight under an atmosphere of hydrogen.The reaction mixture was filtered on celite and the filtrate wasconcentrated under reduced pressure. The resulting oil was evaporatedunder high vacuum overnight to afford the title compound (1.478 g, 2.477mmol, 96% yield). LCMS RT=1.12 min, ES+ve m/z 619.3 [M+Na]⁺.

Example 1 Alternative Synthesis(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide

tert-Butyl2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(100 mg, 0.168 mmol) was dissolved in 1,4-dioxane (2 mL). HCl in dioxane(4M, 0.210 mL, 0.840 mmol) was added and the reaction mixture wasstirred at 40° C. for 3 h. A further aliquot of HCl in dioxane (4M,0.210 mL, 0.840 mmol) was added and the reaction mixture was stirred at40° C. overnight. The reaction mixture was concentrated under reducedpressure. The residue was dissolved in acetonitrile and concentratedunder reduced pressure (this process was done twice) to give thecarboxylic acid intermediate (80 mg). HATU (77 mg, 0.203 mmol) was addedto a solution of the obtained intermediate (80 mg), DIPEA (0.2 mL, 1.145mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide(94 mg, 0.218 mmol) in N,N-dimethylformamide (1.5 mL). The reactionmixture was stirred for 45 min at room temperature. The crude mixturewas directly subjected to purification by mass-directed automatedpreparative HPLC (formic acid modifier) to afford the title compound (50mg, 0.052 mmol, 31% yield). LCMS RT=1.04 min, ES+ve m/z 953.7 [M+H]⁺.

(2S,4R)—N-(4-Chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide,hydrochloride

HATU (1676 mg, 4.41 mmol) was added portionwise to a solution of(2S,4R)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidine-2-carboxylic acid(commercially available from for example Aldrich) (1.019 g, 4.41 mmol),(4-chlorophenyl)methanamine (commercially available from for exampleAldrich) (520 mg, 3.67 mmol) and DIPEA (1.924 mL, 11.02 mmol) in DMF (20mL). The reaction was stirred at room temperature for 3 h. The reactionmixture was partitioned between EtOAc (100 mL) and water (100 mL). Theaqueous phase was back extracted with EtOAc (100 mL) and the organicphase was dried with MgSO₄. The combined organic extracts were driedusing a hydrophobic frit and concentrated under reduced pressure. Theresidue was purified by chromatography on silica using a gradientelution from 0 to 50% MeOH in TBME to afford the required intermediate(1.053 g). The obtained compound was dissolved in HCl in dioxane (4M, 10mL, 40 mmol) and the solution was stirred for 30 min. MeOH (10 mL) wasadded to solubilise the white suspension and the reaction mixture wasstirred for further 30 min. The solvent was concentrated under reducedpressure to give a white solid. MeOH was added and the product wasconcentrated under reduced pressure (this process was done twice) toafford the title compound (895 mg, 3.07 mmol, 84% yield) as a whitesolid. LCMS RT=0.54 min, ES+ve m/z 255.2 [M+H]⁺.

(2S,4R)-1-((S)-2-Amino-3,3-dimethylbutanoyl)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide,hydrochloride

HATU (1.603 g, 4.22 mmol) was added portionwise to a solution of(S)-2-((tert-butoxycarbonyl)amino)-3,3-dimethylbutanoic acid (975 mg,4.22 mmol),(2S,4R)—N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide,hydrochloride (895 mg, 3.07 mmol) and DIPEA (1.841 mL, 10.54 mmol) inDMF (40 mL). The reaction was stirred for 45 min at room temperature.The reaction mixture was partitioned between EtOAc (200 mL) and water(200 mL). The aqueous phase was back extracted with EtOAc (200 mL) andthe combined organic phases were washed with brine (200 mL). The organicphase was dried using a hydrophobic frit and concentrated under reducedpressure. The residue was purified by chromatography on silica using agradient elution from 0 to 25% MeOH in methyl tert-butyl ether to affordthe required intermediate (500 mg). The obtained compound was stirred inHCl in dioxane (4M, 10 mL, 40 mmol) at room temperature for 1 h. Thereaction mixture was concentrated under reduced pressure. The residuewas dried under high vacuum for 48 h to afford the title compound (396mg, 0.979 mmol, 32% yield), as a white solid. LCMS RT=0.63 min, ES+vem/z 368.2 [M+H]⁺.

Example 30(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide

tert-Butyl2-(2-(2-(2-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)ethoxy)ethoxy)ethoxy)acetate(100 mg, 0.168 mmol) was dissolved in HCl in dioxane (4M, 2 mL, 8 mmol).The reaction was stirred 3 h. The reaction mixture was concentratedunder reduced pressure. The residue was dissolved in acetonitrile thenconcentrated under reduced pressure (this process was done twice) togive the carboxylic acid intermediate (80 mg). HATU (70 mg, 0.184 mmol)was added to a solution of the obtained intermediate (80 mg), DIPEA (0.2mL, 1.145 mmol) and(2S,4R)-1-((S)-2-amino-3,3-dimethylbutanoyl)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide,hydrochloride (70 mg, 0.173 mmol) in DMF (1.5 mL). The mixture wasstirred at room temperature overnight. The crude mixture was directlysubjected to purification by mass-directed automated preparative HPLC(formic acid modifier) to afford the title compound (50 mg, 0.056 mmol,34% yield). LCMS RT=1.11 min, ES+ve m/z 889.0 [M−H]⁻.

Estrogen Receptor Alpha (ERa) Degradation and Cell Count Imaging Assay

Compounds were assessed for ERa degradation and cell count effects in anMCF-7 cell line using high content imaging. 50 ul of MCF-7 cellsuspension in media was dispensed to each well of black walled, clearbottomed, PDL-coated plates, containing a defined concentration of testcompound dissolved in DMSO covering concentration range from 0.03 uM to30 uM. Cells were incubated in the presence of compound for 24 hours at37° C., 5% CO₂ before cells were fixed. After incubation with thefixative solution (4% formaldehyde) the wells were aspirated and asolution containing detergent was added to permeabilise the cellsfollowed by addition of blocking solution containing 1% BSA (bovineserum albumin) to block the non-specific binding sites. After a furtherincubation for 1 hour this solution was aspirated from the wells and theERa specific antibody diluted in blocking solution at concentration 1ug/ml (anti ERa, cat no sc-543, Santa Cruz) was added. Followingincubation with the antibody for 2 hours the cells were washed with aPBS-based solution before addition of a secondary anti rabbitfluorescently-labelled Alexa Fluor 488 goat antibody at 2 ug/mlconcentration (cat no11008, Invitrogen) and a nuclear staining dyeHoechst33342 at 1 ug/ml concentration (cat no H3570, invitrogen).Following a further incubation for 1 hour the cells were again washedwith the PBS-based solution. The plates were then imaged and theintensity of ERa staining in the nucleus and cell count measured. ERadegradation activity was expressed relative to DMSO, giving 0%degradation, and an in-house degrader molecule classified as giving 100%activity. Cell count reduction was expressed relative to DMSO,classified as 0% reduction.

Examples showed evidence of ERa degradation in this assay relative tothe DMSO control at 1 uM concentration.

What is claimed is:
 1. A compound of formula (I):

wherein R¹ is OH, OC₁₋₃alkyl, halogen, or H R₂ is OH, or OC₁₋₃alkyl X isO, or CO L is a linking group comprising a length of 8-16 atoms inlength R₃ is straight or branched chain C₁₋₆alkyl, or C₃₋₆ cycloalkyl R₄is 4-methylthiazol-5-yl, oxazol-5-yl, or halo or a pharmaceuticallyacceptable salt thereof.
 2. A compound or a pharmaceutically acceptablesalt thereof according to claim 1 wherein R4 is 4-methylthiazol-5-yl, oroxazol-5-yl.
 3. A compound or a pharmaceutically acceptable salt thereofaccording to claim 2 wherein R₄ is 4-methylthiazol-5-yl.
 4. A compoundor a pharmaceutically acceptable salt thereof according to claim 1wherein R₄ is chloro.
 5. A compound or a pharmaceutically acceptablesalt thereof according to claim 2 wherein R₄ is oxazol-5-yl.
 6. Acompound or a pharmaceutically acceptable salt thereof according toclaim 1 wherein R¹ is OH, F, Br, OCH₃ or H.
 7. A compound or apharmaceutically acceptable salt thereof according to claim 6 wherein R¹is OH.
 8. A compound or a pharmaceutically acceptable salt thereofaccording to claim 1 wherein R₂ is OH or OCH₃.
 9. A compound or apharmaceutically acceptable salt thereof according to claim 8 wherein R²is OH.
 10. A compound or a pharmaceutically acceptable salt thereofaccording to claim 1 wherein the linker group is a straight chainalkylene group of 8-16 carbon atoms wherein one or more carbon atoms arereplaced by a group each independently selected from —O—, —NH—,—N(CH₃)—,


11. A compound or a pharmaceutically acceptable salt thereof accordingto claim 10 wherein the linker group is of formula (ii)—(R⁵CH₂CH₂)X OCH₂  (ii) wherein each R⁵ is independently selected from—O—, —NH—, —N(CH₃)— or

 and x is 2-4.
 12. A compound or a pharmaceutically acceptable saltthereof according to claim 1 wherein the linker is selected from(OCH₂CH₂)₄OCH₂ (OCH₂CH₂)₃OCH₂ (OCH₂CH₂)₂OCH₂

OCH₂CH₂N(CH₃)CH₂CH₂OCH₂CH₂OCH₂ OCH₂CH₂N(CH₃)(CH₂)₃(OCH₂CH₂)₂OCH₂


13. A compound of formula (I) according to claim 1 which is selectedfrom the group consisting of(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-phenylbenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-14-(4-((2-(4-Bromophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)-2-(tert-butyl)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((2-(4-fluorophenyl)-6-hydroxybenzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-methyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-Ethyl-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-Cyclopropyl-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-Cyclopentyl-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-isobutyl-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-2-isopropyl-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(2-(4-Hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(6-hydroxy-2-(4-methoxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-4-hydroxy-N-(4-(oxazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-12-methyl-4-oxo-6,9-dioxa-3,12-diazatetradecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-18-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)-16-methyl-4-oxo-6,9,12-trioxa-3,16-diazaoctadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(2-(4-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)piperazin-1-yl)ethoxy)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(4-(2-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenoxy)ethyl)piperazin-1-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2-(2-(4-(1-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyephenyl)piperidin-4-yl)piperazin-1-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-4-Hydroxy-1-((S)-2-(2-(2-(9-(4-(6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophene-3-carbonyl)phenyl)-3,9-diazaspiro[5.5]undecan-3-yl)ethoxy)acetamido)-3,3-dimethylbutanoyl)-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-17-(4-(2-(4-hydroxyphenyl)-6-methoxybenzo[b]thiophene-3-carbonyl)phenoxy)-4-oxo-6,9,12,15-tetraoxa-3-azaheptadecan-1-oyl)-4-hydroxy-N-(4-(4-methylthiazol-5-yl)benzyl)pyrrolidine-2-carboxamide;(2S,4R)-1-((S)-2-(tert-Butyl)-14-(4-((6-hydroxy-2-(4-hydroxyphenyl)benzo[b]thiophen-3-yl)oxy)phenoxy)-4-oxo-6,9,12-trioxa-3-azatetradecan-1-oyl)-N-(4-chlorobenzyl)-4-hydroxypyrrolidine-2-carboxamide;and pharmaceutically acceptable salts thereof.
 14. A pharmaceuticalcomposition comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof according to claim 1 and one or more ofpharmaceutically acceptable carriers, diluents and excipients.
 15. Amethod of treating a proliferative disease or condition mediated byincreased estrogen receptor-alpha (ERα) activity in a subject whereinthe proliferative disease or condition is selected from breast cancer,uterine cancer, or endometriosis, comprising administering to a subjectin need thereof a therapeutically effective amount of a compound offormula (I) or a pharmaceutically acceptable salt thereof according toclaim 1, wherein the compound is effective for treating theproliferative disease.
 16. A combination comprising a compound offormula (I) or a pharmaceutically acceptable salt thereof according toclaim 1 and at least one anti-neoplastic therapeutic agent.
 17. Acombination comprising a compound of formula (I) or a pharmaceuticallyacceptable salt thereof according to claim 1 and at least oneanti-neoplastic agent.
 18. A method of treating a proliferative diseaseor condition mediated by increased estrogen receptor-alpha (ERα)activity, wherein the proliferative disease or condition is selectedfrom breast cancer, uterine cancer, or endometriosis, comprisingadministering to a human in need thereof a therapeutically effectiveamount of a combination comprising a compound of formula (I) or apharmaceutically acceptable salt thereof according to claim 1 and atleast one anti-neoplastic agent, wherein the combination is effectivefor treating the proliferative disease.
 19. A pharmaceutical compositioncomprising a compound of formula (I) or a pharmaceutically acceptablesalt thereof according to claim 1 and at least one anti-neoplastic agentand one or more of pharmaceutically acceptable carriers, diluents andexcipients.
 20. A method of treating breast cancer comprisingadministering to human in need thereof, a therapeutically effect amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof according to claim
 1. 21. A method of degrading the estrogenreceptor comprising administration comprising administering to a humanin need thereof a therapeutically effective amount of a compound ofFormula (I) according to claim 1 or a pharmaceutically acceptable saltthereof.